Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of bruton&#39;s tyrosine kinase by such compounds

ABSTRACT

Compounds of Formula I-a  
                 
and all pharmaceutically-acceptable forms thereof, are described herein.  
     The variables R 1 , R 2 , R 3 , Z 1 , Q, and A shown in Formula I-a are defined herein. Pharmaceutical compositions containing one or more compounds of Formula I-a, or a pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents are provided herein. Methods of treating patients suffering from certain diseases responsive to inhibition of tyrosine kinase activity are also given. In certain embodiments the diseases are responsive to inhibition of Btk activity and/or B-cell proliferation. Such methods comprise administering to such patients an amount of a compound of Formula I-a effective to reduce signs or symptoms of the disease. These diseases include cancer, an autoimmune and/or inflammatory disease, or an acute inflammatory reaction. Thus methods of treatment include administering a sufficient amount of a compound or salt as provided herein to decrease the symptoms or slow the progression of these diseases. Other embodiments include methods of treating other animals, including livestock and domesticated companion animals, suffering from a disease responsive to inhibition of kinase activity. Methods of treatment include administering a compound of Formula I-a as a single active agent or administering a compound of Formula I-a in combination with one or more other therapeutic agent. A method for determining the presence of Btk in a sample, comprising contacting the sample with a compound or form thereof of Formula I-a under conditions that permit detection of Btk activity, detecting a level of Btk activity in the sample, and therefrom determining the presence or absence of Btk in the sample.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to US provisional application60/475,634 filed Jun. 4, 2003, and US provisional application 60/519,311filed Nov. 11, 2003, which are hereby incorporated by reference in theirentirety.

FIELD OF INVENTION

Certain imidazo[1,2-a]pyrazin-8-ylamine and related compounds, whichwhen appropriately substituted are inhibitors of tyrosine kinaseactivity, including Bruton's tyrosine kinase (Btk) activity, areprovided herein. Certain compounds provided herein are highly activeand/or specific inhibitors of Btk activity. Pharmaceutical compositionscomprising such compounds, and methods of using certainimidazo[1,2-a]pyrazin-8-ylamine and related compounds to treat a varietyof diseases responsive to inhibition of Btk activity and/or inhibitionof B-cell proliferation, are also disclosed. Additionally, methods forusing such compounds as probes for the detection and/or localization ofBtk in biological samples are given.

BACKGROUND

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Kinases play critical roles in signaling pathwayscontrolling fundamental cellular processes such as proliferation,differentiation, and death (apoptosis). Abnormal kinase activity hasbeen implicated in a wide range of diseases, including multiple cancersand autoimmune and inflammatory diseases. The multifaceted role ofkinases in key cell signaling pathways provides a significantopportunity to identify novel drugs targeting kinases and signalingpathways. Diseases mediated by receptor kinase activity include, but arenot limited to, diseases characterized in part by abnormal levels ofcell proliferation (i.e. tumor growth), programmed cell death(apoptosis), cell migration and invasion, and angiogenesis associatedwith tumor growth.

Because kinases are key regulators they are ideal drug design targets.Inhibitors of kinases are among the most important classes ofpharmaceutical compounds known. Highly specific, cell-permeableinhibitors of one or more individual kinases are useful for thetreatment of various kinase-implicated diseases. Kinase inhibitingcompounds are additionally useful for the systematic investigation ofthe cellular function of one or more kinases, and thus, provide valuabletools for the identification of various kinases of therapeutic interest.

Bruton's Tyrosine Kinase (Btk) is a member of the Tec family of tyrosinekinases, and is a critical regulator of early B-cell development as wellas mature B-cell activation, signaling and survival.

B-cell signaling through the B-cell receptor (BCR) leads to a wide rangeof biological outputs, which in turn depend on the developmental stageof the B-cell. The magnitude and duration of BCR signals must beprecisely regulated. Aberrant BCR-mediated signaling can causedisregulated B-cell proliferation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the impairedmaturation of B-cells, diminished immunoglobulin production, comprisedT-cell-independent immune responses and marked attenuation of thesustained calcium sign upon BCR stimulation.

Evidence for the role of Btk in autoimmune and/or inflammatory diseasehas been established in Btk-deficient mouse models. For example, instandard murine preclinical models of systemic lupus erythematosus(SLE), Btk deficiency has been shown to result in a marked ameliorationof disease progression. Moreover, Btk deficient mice are also resistantto developing collagen-induced arthritis and are less susceptible toStaphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as Rituxan) developed todeplete B-cells, represent an important approach to the treatment of anumber of autoimmune and/or inflammatory diseases. Because of Btk's rolein B-cell activation, inhibitors of Btk are useful as inhibitors ofB-cell mediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown tobe important for the function of these cells. For example, Btkdeficiency in mice is associated with impaired IgE-mediated mast cellactivation (marked diminution of TNFα and other inflammatory cytokinerelease), and greatly reduced TNFα production by activated monocytes.

Thus, inhibition of Btk activity is useful for the treatment ofautoimmune and/or inflammatory diseases such as: SLE, rheumatoidarthritis, multiple vasculitides, idiopathic thrombocytopenic purpura(ITP), myasthenia gravis, and asthma. In addition, Btk has been reportedto play a role in apoptosis, thus inhibition of Btk activity is usefulfor the treatment of B-cell lymphoma and leukemia.

Agents capable of inhibiting Btk kinase activity, are highly desirablefor the treatment of a variety of diseases, including cancer, anautoimmune and/or inflammatory disease, or an acute inflammatoryreaction. Specific, cell-penetrating, small molecule, non-peptideantagonists of Btk are of particular value for such therapies. Suchcompounds are also useful for the systematic investigation of thecellular function of Btk, and thus, are valuable research tools for theidentification of cell signalling proteins of therapeutic interest.

The present invention fulfills this need, and provides further relatedadvantages.

SUMMARY

Inhibitors of kinase activity, which may generally be described asimidazo[1,2-a]pyrazin-8-ylamines and related compounds, are disclosedherein. Certain compounds provided herein are highly active and/orspecific inhibitors of Btk (Bruton's tyrosine kinase) activity.

One embodiment provides a compound of Formula I-a

or a pharmaceutically acceptable form thereof

-   -   Within Formula I-a:    -   A is 0 or 1.    -   R₁ is phenyl or heteroaryl, each of which is optionally        substituted with one of    -   (i) oxo, —CHO, —COOH, —CONH₂, or —CONHOH,    -   (ii) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,        C₁-C₆hydroxyalkoxy, (mono- or di-C₁-C₆alkylamino)C₁-C₆alkoxy,        (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,        (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, heterocycloalkyl, aryl,        or heteroaryl,    -   (iii) —C₁-C₆alkyl(C═O)OR₁₀, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,        —C₁-C₆alkylNR₁₀(SO₂)R₁₁, —C₀-C₆alkylNR₁₀(C═O)R₁₁,        —C₀-C₆alkyl(SO₂)R₁₀, or —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ where R₁₀,        R₁₁ , and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,        C₁-C₆alkoxy, C₃-C₁₀-cycloalkyl, or heterocycloalkyl, or    -   (iv) -L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or        —(C₁-C₂alkyl)(C═O)—, and G is heterocycloalkyl, C₃-C₇cycloalkyl,        aryl, or heteroaryl.

Each of which (ii), (iii), and (iv) is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- anddi-C₁-C₄alkylcarboxamide, and phenyl.

And, R₁ is substituted with 0 or 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.

R₂ is C₁-C₇ alkyl, (C₁-C₆alkoxy)C₀-C₆alkoxy,(heterocycloalkyl)C₀-C₂alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, or R₂ is(phenyl)C₀-C₂alkyl, (phenoxy)C₀-C₂alkyl, or (heteroaryl)C₀-C₂alkyl, eachof which is substituted with 0 to 3 substituents independently chosenfrom hydroxy, nitro, cyano, amino, halogen, —SO₂NH₂, oxo, —COOH, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₂-C₆alkanoyl,C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆alkyl, mono- anddi-C₁-C₆alkylamino, mono- and di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, and heteroaryl, and —(C═O)R₁₃ wherein R₁₃is C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, or heteroaryl.

Z₁ is

wherein R₄ is hydrogen, or R₄ is C₁-C₆alkyl, C₃-C₇cycloalkyl,heterocycloalkyl, phenyl, or heteroaryl, each of which is substitutedwith 0 or 1 or more substituents independently chosen from hydroxy,nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono- anddi-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is C₁-C₆ alkyl,C₁-C₃haloalkyl, or phenyl.

-   -   Q is phenyl or pyridyl.    -   R₃ is hydrogen, C₁-C₇ alkyl, or halogen, or    -   R₃ is heterocycloalkyl, C₃-C₇cycloalkyl, or heteroaryl, each of        which is substituted with from 0 to 3 substituents independently        chosen from hydroxy, nitro, cyano, amino, halogen, —SO₂NH₂, oxo,        C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,        C₁-C₃halooalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,        (C₁-C₆-alkoxy)C₁-C₆ alkoxy, mono- and di-C₁-C₆alkylamino,        aminoC₁-C₆ alkyl, and —C(O)R₁₄.

In certain embodiments compounds of Formula I-a, which exhibit an IC₅₀of 1 micromolar or less, 100 nanomolar or less, or 10 nanomolar or lessin standard biochemical assay for Btk activity, such as the biochemicalassay described in Example 6, are provided herein. Preferred compoundsdescribed herein are highly active inhibitors of B-cell proliferation.For example certain compounds described herein exhibit an IC₅₀ valueless than or equal to 10 micromolar, or an IC₅₀ value less than or equalto 1 micromolar, or an IC₅₀ value less than or equal to 500 nM in thetritiated thymidine incorporation assay for B-cell proliferationdescribed in Example 8. Preferred compounds described herein arespecific inhibitors of B-cell proliferation, exhibiting an IC₅₀ valuethat is at least 3-fold, preferably 5-fold, and more preferably 10-foldgreater for T-cell proliferation than the IC₅₀ for B-cell proliferation.The IC₅₀ for T-cell proliferation may be determined via a standard assayfor T-cell proliferation such as the thymidine incorporation assay ofExample 9.

A method for determining the presence of Btk in a sample, comprisingcontacting the sample with a compound or form thereof of Formula I-aunder conditions that permit detection of Btk activity, detecting alevel of Btk activity in the sample, and therefrom determining thepresence or absence of Btk in the sample, is also provided herein.

Pharmaceutical compositions, comprising one or more compounds of FormulaI-a, or any pharmaceutically acceptable form thereof, together with atleast one pharmaceutically acceptable carrier or excipient, are providedherein.

Other embodiments pertain to packaged pharmaceutical compositions whichcomprise a pharmaceutical composition, comprising one or more compoundsof Formula I-a or any pharmaceutically acceptable form thereof, togetherwith at least one pharmaceutically acceptable carrier or excipient in acontainer and with instructions for using the pharmaceutical compositionto treat a patient. Preferably the instructions are for using thepharmaceutical composition to treat a patient suffering from a diseaseresponsive to inhibition of Btk activity.

Still other embodiments pertain to a method of inhibiting Btk kinase. Incertain embodiments the method comprises contacting a cell or cellsexpressing Btk, either in vivo or in vitro, with a compound of FormulaI-a or form thereof in an amount sufficient to detectably inhibit Btkactivity in vitro.

Inhibiting Btk activity can effectively inhibit B-cell proliferation.Small molecule (less than 600 amu) Btk inhibitors that are orallybioavailable, such as certain compounds and forms of Formula I-a, areparticularly desirable for this purpose. Thus a method of inhibitingB-cell proliferation, by contacting cells expressing Btk, either in vivoor in vitro with a compound having a molecular weight less than 600 amuin an amount sufficient to detectably inhibit the activity of Btk invitro is provided herein. In certain embodiments the compound will be aheterocyclic compound, such as a heterocyclic compound having a bicyclicheterocyclic group. In certain embodiments the compound is a compound ofFormula I-a.

A method of treating a mammal suffering from at least one diseaseresponsive to inhibition of Btk activity, by administering to the mammalan effective amount of a compound that is a highly active Btk inhibitorin an in vitro assay of Btk activity is included herein. Preferably thecompound is also a specific inhibitor of B-cell proliferation,exhibiting an IC₅₀ value that is at least 3-fold, preferably 5-fold, andmore preferably 10-fold greater for T-cell proliferation than the IC₅₀value for B-cell proliferation.

Methods for treating a patient having a disease responsive to inhibitionof Btk activity and/or responsive to inhibition of B-cell proliferation,are provided herein. Such methods comprise administering to the patientan effective amount of a compound or form thereof of Formula I-a. Thepatient may be a mammal. Preferably the patient is a human patient,however methods of treating non-human patients are included herein. Forexample in some embodiments the patient is a companion animal, such as acat or dog, or the patient is a livestock animal, such as a horse, cow,or pig. Particularly included herein are methods in which the diseaseresponsive to Btk inhibition is cancer, an autoimmune and/orinflammatory disease, or an acute inflammatory reaction.

Methods of treatment include administering a compound of Formula I-a asa single active agent or administering a compound of Formula I-a incombination with one or more other active agents.

DETAILED DESCRIPTION

Certain terms to be used herein are provided prior to setting forth theinvention in detail. Compounds of the present invention are describedusing standard nomenclature. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as is commonlyunderstood by one of skill in the art to which this invention belongs.

Chemical Description and Terminology

Formula I-a includes all subformulae thereof. For example Formula I-aincludes compounds of Formulas 1 to 9.

Certain compounds are described herein using a general formula thatincludes variables, e.g. R₁, R₂, R₃, Q, Z₁, and A. Unless otherwisespecified, each variable within such a formula is defined independentlyof other variables. When any variable occurs more than one time inFormula I-a, its definition on each occurrence is independent of itsdefinition at every other occurrence.

In accordance with the usual meaning of “a” and “the” in patents,reference to “a” kinase or “the” kinase is inclusive of one or morekinases. Unless otherwise specified the term “compounds” includes allpharmaceutically acceptable forms of the disclosed structures.

In certain situations, the compounds of Formula I-a may contain one ormore asymmetric elements such as stereogenic centers, stereogenic axesand the like, e.g. asymmetric carbon atoms, so that the compounds canexist in different stereoisomeric forms. These compounds can be, forexample, racemates or optically active forms. For compounds with two ormore asymmetric elements, these compounds can additionally be mixturesof diastereomers. For compounds having asymmetric centers, it should beunderstood that all of the optical isomers and mixtures thereof areencompassed. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E-forms, with all isomeric forms of the compounds beingincluded in the present invention. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis, synthesis from optically pure precursors, or by resolution ofthe racemates. Resolution of the racemates can also be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralHPLC column.

Where a compound exists in various tautomeric forms, the invention isnot limited to any one of the specific tautomers, but rather includesall tautomeric forms.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample, and without limitation, isotopes of hydrogen include tritiumand deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When the substituent is oxo (i.e., ═O), then 2hydrogens on the atom are replaced. When aromatic moieties aresubstituted by an oxo group, the aromatic ring is replaced by thecorresponding partially unsaturated ring. For example a pyridyl groupsubstituted by oxo is a pyridone. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulationinto an effective therapeutic agent.

Suitable groups that may be present on a “substituted” position include,but are not limited to, e.g., halogen; cyano; hydroxyl; nitro; azido;alkanoyl (such as a C₂-C₆ alkanoyl group such as acyl or the like);carboxamido; alkyl groups (typically having 1 to about 8 carbon atoms,or 1 to about 6 carbon atoms); cycloalkyl groups, alkenyl and alkynylgroups (including groups having one or more unsaturated linkages andfrom 2 to about 8, or 2 to about 6 carbon atoms); alkoxy groups havingone or more oxygen linkages and from 1 to about 8, or from 1 to about 6carbon atoms; aryloxy such as phenoxy; alkylthio groups including thosehaving one or more thioether linkages and from 1 to about 8 carbonatoms, or from 1 to about 6 carbon atoms; alkylsulfinyl groups includingthose having one or more sulfinyl linkages and from 1 to about 8 carbonatoms, or from 1 to about 6 carbon atoms; alkylsulfonyl groups includingthose having one or more sulfonyl linkages and from 1 to about 8 carbonatoms, or from 1 to about 6 carbon atoms; aminoalkyl groups includinggroups having one or more N atoms and from 1 to about 8, or from 1 toabout 6 carbon atoms; aryl having 6 or more carbons and one or morerings, (e.g., phenyl, biphenyl, naphthyl, or the like, each ring eithersubstituted or unsubstituted aromatic); arylalkyl having 1 to 3 separateor fused rings and from 6 to about 18 ring carbon atoms, with benzylbeing an exemplary arylalkyl group; arylalkoxy having 1 to 3 separate orfused rings and from 6 to about 18 ring carbon atoms, with benzyloxybeing an exemplary arylalkoxy group; or a saturated, unsaturated, oraromatic heterocyclic group having 1 to 3 separate or fused rings with 3to about 8 members per ring and one or more N, O, or S atoms, e.g.coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl,pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl,isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl,piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be furthersubstituted, e.g. with hydroxy, alkyl, alkoxy, halogen or amino.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CHO isattached through carbon of the carbonyl (C═O) group.

As used herein, “alkyl” includes both branched and straight chainsaturated aliphatic hydrocarbon groups, having the specified number ofcarbon atoms, generally from 1 to about 12 carbon atoms. The termC₁-C₇alkyl as used herein indicates an alkyl group having from 1 to 7carbon atoms. When C₀-C_(n)alkyl is used herein in conjunction withanother group, for example, (heterocycloalkyl)C₀-C₂alkyl, the indicatedgroup, in this case heterocycloalkyl, is either directly bound by asingle covalent bond (C₀), or attached by an alkyl chain having thespecified number of carbon atoms, in this case from 1 to 2 carbon atoms.Examples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, andsec-pentyl. Alkyl groups described herein typically have from 1 to about12 carbons atoms. Preferred alkyl groups are lower alkyl groups, thosealkyl groups having from 1 to about 8 carbon atoms, from 1 to about 6carbon atoms, or from 1 to about 4 carbons atoms e.g. C₁-C₈, C₁-C₆, andC₁-C₄alkyl groups.

“Alkenyl” as used herein, indicates a straight or branched hydrocarbonchain comprising one or more unsaturated carbon-carbon bonds, which mayoccur in any stable point along the chain. Alkenyl groups describedherein typically have from 2 to about 12 carbons atoms. Preferredalkenyl groups are lower alkenyl groups, those alkenyl groups havingfrom 2 to about 8 carbon atoms, e.g. C₂-C₈, C₂-C₆, and C₂-C₄ alkenylgroups. Examples of alkenyl groups include ethenyl, propenyl, andbutenyl groups.

“Alkynyl” as used herein, indicates a straight or branched hydrocarbonchain comprising one or more triple carbon-carbon bonds that may occurin any stable point along the chain, such as ethynyl and propynyl.Alkynyl groups described herein typically have from 2 to about 12carbons atoms. Preferred alkynyl groups are lower alkynyl groups; thosealkynyl groups having from 2 to about 8 carbon atoms, e.g. C₂-C₈, C₂-C₆,and C₂-C₄ alkynyl groups.

“Alkoxy” indicates an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge (—O—). Examplesof alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy,3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy.

In the term “(Alkoxy)alkyl” alkoxy and alkyl are as defined above andthe point of attachment is on the alkyl group. For example(C₁-C₆alkoxy)C₁-C₆alkyl indicates an alkoxy group having from 1 to about6 carbon atom attached through its oxygen atom to an alkyl group havingfrom 1 to about 6 carbon atoms and further attached to the core moleculethrough a carbon atom in the C₁-C₆alkyl portion.

In the term “(Alkoxy)alkoxy” alkoxy is as defined above and the point ofattachment is on the oxygen of the second listed alkoxy group. Forexample (C₁-C₆alkoxy)C₁-C₄alkoxy indicates an alkoxy group have from 1to about 6 carbon atom attached through its oxygen atom to an secondalkoxy group, this one having, for example, from 1 to about 4 carbonatoms, and further attached to the core molecule through an oxygenbridge. Similarly the term “(alkoxy)(alkoxy)alkoxy” refers to two suchalkoxy groups attached to a third alkoxy, which is further attached tothe core molecule through an oxygen bridge.

“Alkanoyl” indicates an alkyl group as defined above, attached through aketo (—(C═O)—) bridge. Alkanoyl groups have the indicated number ofcarbon atoms, with the carbon of the keto group being included in thenumbered carbon atoms. For example a C₂alkanoyl group is an acetyl grouphaving the formula CH₃(C═O)—.

As used herein, “alkylthio” means alkyl-S—, where the alkyl group is analkyl group as defined above having the defined number of carbon atoms.An exemplary alkylthio group is methylthio.

As used herein the term “alkoxycarbonyl” indicates an alkoxy group, asdefined above, having the indicated number of carbon atoms, attachedthrough a keto (—(C═O)—) bridge. The alkoxy moiety of the alkoxycarbonylgroup has the indicated number of carbon atoms. The carbon of the ketobridge is not included in this number. C₃alkoxycarbonyl indicates forexample, groups of the formula CH₃(CH₂)₂—O—(C═O)—or (CH₃)₂(CH)—O—(C═O)—.

As used herein “aminoalkyl” is an alkyl group as defined herein, havingthe indicated number of carbon atoms, and substituted with at least oneamino substituent (—NH₂). When indicated, aminoalkyl groups, like othergroups described herein, may be additionally substituted.

As used herein, the term “mono- and/ or di-alkylamino” indicatessecondary or tertiary alkylamino groups, wherein the alkyl groups are asdefined above and have the indicated number of carbon atoms. The pointof attachment of the alkylamino group is on the nitrogen. The alkylgroups are independently chosen. Examples of mono- and/ or di-alkylaminogroups include ethylamino, dimethylamino, and methyl-propyl-amino.“Mono- and/or di-alkylaminoalkyl” groups are mono- and/ or di-alkylaminogroups attached through an alkyl linker having the specified number ofcarbon atoms, for example a di-methylaminoethyl group. Tertiary aminosubstituents may by designated by nomenclature of the form N—R—N—R′,indicating that the groups R and R′ are both attached to a singlenitrogen atom.

As used herein, the term “mono- and/ or di-(alkylamino)alkyl” indicatesa mono- and/or di-alkylamino group as defined attached through an alkyllinker having the specified number of carbon atoms. Similarly “mono-and/ or di-(alkylamino)alkoxy” indicates a mono- and/or di-alkylaminogroup as defined attached through an alkoxy linker having the specifiednumber of carbon atoms.

As used herein the term “mono- and/ or di-alkylcarboxamide” refers togroups of formula (alkyl₁)—NH—(C═O)—and (alkyl₁)(alkyl₂)—N—(C═O)—inwhich the alkyl₁ and alkyl₂ groups are independently chosen alkyl groupsas defined above having the indicated number of carbon atoms.“Carboxamide” is a group of the formula —(C═O)NH₂.

As used herein, the term “aryl” indicates aromatic groups containingonly carbon in the aromatic ring or rings. Such aromatic groups may befurther substituted with carbon or non-carbon atoms or groups. Typicalaryl groups contain 1 or 2 separate, fused, or pendant rings and from 6to about 12 ring atoms, without heteroatoms as ring members. Whereindicated, aryl groups may be substituted. Such substitution may includefusion to a 5 to 7-membered saturated cyclic group that optionallycontains 1 or 2 heteroatoms independently chosen from N, 0, and S, toform, for example, a 3,4-methylenedioxy-phenyl group. Aryl groupsinclude, for example, phenyl, naphthyl, including 1-naphthyl and2-naphthyl, and bi-phenyl.

“Cycloalkyl” as used herein, indicates a monocyclic or multicyclicsaturated hydrocarbon ring group, having the specified number of carbonatoms, usually from 3 to about 10 ring carbon atoms. Monocycliccycloalkyl groups typically have from 3 to about 8 carbon ring atoms orfrom 3 to about 7 carbon ring atoms. Multicyclic cycloalkyl groups mayhave 2 or 3 fused cycloalkyl rings or contain bridged or cagedcycloalkyl groups. Cycloalkyl substituents may be pendant to thesubstituted nitrogen or carbon atom, or where a substituted carbon atommay have two substituents a cycloalkyl group may be attached as a spirogroup. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl as well as bridged or caged saturated ringgroups such as norbornane or adamantane.

As used herein “(cycloalkyl)C₀-C₂alkyl indicates a cycloalkyl groups asdefined above either directly attached via a single covalent bond orattached through an ethylene (—CH₂CH₂—) or methylene (—CH₂—) linker.

As used herein “haloalkyl” indicates both branched and straight-chainalkyl groups having the specified number of carbon atoms, substitutedwith 1 or more halogen atoms, generally up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl include, but are notlimited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, andpenta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined above attachedthrough an oxygen bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo,and/or iodo.

As used herein, “heteroaryl” indicates a stable 5- to 7-memberedmonocyclic aromatic ring which contains from 1 to 4, or preferably from1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atomsbeing carbon, or a stable bicyclic or tricyclic system containing atleast one 5 to 7 membered aromatic ring which contains from 1 to 4, orpreferably from 1 to 2, heteroatoms chosen from N, O, and S, withremaining ring atoms being carbon. When the total number of S and Oatoms in the heteroaryl group exceeds 1, these heteroatoms are notadjacent to one another. It is preferred that the total number of S andO atoms in the heteroaryl group is not more than 2. It is particularlypreferred that the total number of S and O atoms in the aromaticheterocycle is not more than 1. Examples of heteroaryl groups include,but are not limited to, oxazolyl, pyranyl, pyrazinyl,pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl,pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl,thiophenyl, triazolyl, benzo[d]oxazolyl, benzofuranyl, benzothiazolyl,benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl,imidazolyl, indolyl, and isoxazolyl.

The term “heterocycloalkyl” indicates a saturated monocyclic groupcontaining from 1 to about 3 heteroatoms chosen from N, O, and S, withremaining ring atoms being carbon, or a saturated bicyclic ring systemhaving at least one N, O, or S ring atom with remaining atoms beingcarbon. Monocyclic heterocycloalkyl groups have from 4 to about 8 ringatoms, and more typically have from 5 to 7 ring atoms. Bicyclicheterocycloalkyl groups typically have from about five to about 12 ringatoms. Preferred heterocycloalkyl groups include monocyclicheterocycloalkyl groups that contain from 5 to 7 ring atoms and 1 or 2heteroatoms independently chosen from N, O, and S. Examples ofheterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl,and pyrrolidinyl groups.

In the term “(heterocycloalkyl)alkyl” the groups heterocycloalkyl andalkyl are as defined above and the point of attachment to the corestructure is on the alkyl group.

As used herein “hydroxyalkyl” is an alkyl group as defined herein,having the indicated number of carbon atoms, and substituted with atleast one hydroxyl substituent (—OH). When indicated, hydroxyalkylgroups, like other groups described herein, may be additionallysubstituted. Similarly the term “hydroxyalkoxy” indicates an alkoxygroup as defined herein, having the indicated number of carbon atoms,and substituted with at least one hydroxyl substituent (—OH).

“Pharmaceutically acceptable forms” of the compounds recited hereininclude pharmaceutically acceptable salts, hydrates, solvates, crystalforms, polymorphs, chelates, non-covalent complexes, esters, clathrates,prodrugs, and mixtures of such compounds. Pharmaceutically acceptablesalts are a preferred pharmaceutically acceptable form.

“Pharmaceutically acceptable salts” include derivatives of the disclosedcompounds wherein the parent compound is modified by making non-toxicacid or base salts thereof, and further refers to pharmaceuticallyacceptable solvates of such compounds and such salts. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts and the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, conventional non-toxic acid salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, HOOC—(CH₂)_(n)—COOH where n is0-4, and the like. The pharmaceutically acceptable salts of the presentinvention can be synthesized from a parent compound, a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting free acid forms of these compounds with astoichiometric amount of the appropriate base (such as Na, Ca, Mg, or Khydroxide, carbonate, bicarbonate, or the like), or by reacting freebase forms of these compounds with a stoichiometric amount of theappropriate acid. Such reactions are typically carried out in water orin an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred, where practicable. Lists of additionalsuitable salts may be found, e.g., in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418(1985).

The term “prodrugs” includes any compounds that become compounds ofFormula I-a when administered to a mammalian subject, e.g., uponmetabolic processing of the prodrug. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate and like derivativesof functional groups (such as alcohol or amine groups) in the compoundsof Formula I-a.

The term “active agent” is used to indicate a compound, including anypharmaceutically form thereof, or natural product, which has biologicalactivity. Preferably an “active agent” is a compound havingpharmaceutical utility. For example an active agent may be a compound ofFormula I-a, or an anti-cancer or anti-inflammatory therapeutic, whichis not a compound of Formula I-a.

The term “effective amount” of a compound of this invention means anamount effective, when administered to a human or non-human patient, toprovide a therapeutic benefit such as amelioration of symptoms, slowingof disease progression, or prevention of disease e.g., an effectiveamount may be an amount sufficient to decrease the symptoms of a diseaseresponsive to Btk inhibition, and preferably is an amount sufficient toreduce cancer symptoms, the symptoms of an autoimmune and/orinflammatory disease, or the symptoms of an acute inflammatory reaction.In some embodiments an effective amount of a compound described hereinis an amount sufficient to decrease the number of detectable cancerouscells in an organism, detectably slow or stop the growth of a canceroustumor, or more preferably an amount sufficient to shrink a canceroustumor. In certain circumstances a patient suffering from cancer may notpresent symptoms of being affected. Thus, a therapeutically effectiveamount of a compound is also an amount sufficient to prevent asignificant increase or significantly reduce the detectable level ofcancerous cells or cancer markers in the patient's blood, serum, ortissues. In methods described herein for treating autoimmune and/orinflammatory diseases or acute inflammatory reactions, an effectiveamount may also be an amount sufficient, when administered to a patient,to detectably slow progression of the disease, or prevent the patient towhom the compound is given from presenting symptoms of the autoimmuneand/or inflammatory disease, or acute inflammatory response. In certainmethods described herein for treating autoimmune and/or inflammatorydiseases or acute inflammatory reactions, an effective amount may alsobe an amount sufficient to produce a detectable decrease in the amountof a marker protein or cell type in the patient's blood or serum. Forexample, in some embodiments an effective amount is an amount of acompound described herein sufficient to significantly decrease thenumber of B-cells. In another example, in some embodiments an effectiveamount is an amount of a compound described herein sufficient todecrease the level of anti-acetylcholine receptor antibody in apatient's blood with the disease myasthenia gravis,.

The term “inhibition” indicates a significant decrease in the baselineactivity of a biological activity or process. “Inhibition of Btkactivity” refers to a decrease in Btk activity as a direct or indirectresponse to the presence of a compound of Formula I-a, relative to theactivity of Btk in the absence of the compound. The decrease in activitymay be due to the direct interaction of the compound with Btk, or due tothe interaction of the compound with one or more other factors that inturn affect Btk activity. For example, the presence of the compound maydecrease Btk activity by directly binding to the Btk, by causing(directly or indirectly) another factor to decrease Btk activity, or by(directly or indirectly) decreasing the amount of Btk present in thecell or organism.

Inhibition of Btk activity also refers to observable inhibition of Btkactivity in a standard biochemical assay for Btk activity, such as theATP hydrolysis assay of Example 6. Preferred inhibitors of Btk activityhave an IC₅₀ value less than or equal to 1 micromolar, more preferablyless than or equal to less than 100 nanomolar, and still more preferablyless than or equal to 10 nanomolar.

Without wishing to be bound to any particular theory it is believed thatthe inhibition of Btk activity causes an inhibition of B-cellproliferation. “Inhibition of B-cell proliferation” refers to inhibitionof proliferation of abnormal B-cells, such as cancerous B-cells, e.g.lymphoma B-cells and/or inhibition of normal, non-diseased B-cells. Theterm “inhibition of B-cell proliferation” indicates any significantdecrease in the number of B-cells, either in vitro or in vivo. Thus invitro an inhibition of B-cell proliferation would be any significantdecrease in the number of B-cells in an in vitro sample contacted with acompound of Formula I-a as compared to a matched sample not contactedwith a compound of Formula I-a.

Inhibition of B-cell proliferation also refers to observable inhibitionof B-cell proliferation in a standard thymidine incorporation assay forB-cell proliferation, such as the assay of Example 8. Preferredinhibitors of B-cell proliferation have an IC₅₀ value less than or equalto 10 micromolar, more preferably less than or equal to less than 1micromolar, and still more preferably less than or equal to 500nanomolar.

By “significant” is meant any detectable change that is statisticallysignificant in a standard parametric test of statistical significancesuch as Student's T-test, where p<0.05.

A “disease responsive to Btk inhibition” is a disease in whichinhibiting Btk kinase provides a therapeutic benefit such as anamelioration of symptoms, decrease in disease progression, prevention ordelay of disease onset, or inhibition of aberrant activity of certaincell-types (monocytes, B-cells, and mast cells).

IMIDAZO[1,2-a]PYRAZINE COMPOUNDS

In addition to compounds of Formula I-a (above), compounds of Formula 1

and the pharmaceutically acceptable form thereof, are also disclosed.

-   -   Within Formula 1:    -   A is 0 or 1.    -   R₁ is phenyl or heteroaryl, each of which is substituted with        one of    -   (i) oxo, —CHO, —COOH, —CONH₂, or —CONHOH,    -   (ii) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,        C₁-C₆hydroxyalkoxy, (mono- or di-C₁-C₆alkylamino)C₁-C₆alkoxy,        (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,        (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, heterocycloalkyl, aryl,        or heteroaryl,    -   (iii) —C₁-C₆alkyl(C═O)OR₁₀, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,        —C₁-C₆alkylNR₁₀(SO₂)R₁₁, —C₀-C₆alkylNR₁₀(C═O)R₁₁,        —C₀-C₆alkyl(SO₂)R₁₀, or —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ where R₁₀,        R₁₁, and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,        C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, or heterocycloalkyl, or    -   (iv)-L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or        —(C₁-C₂alkyl)(C═O)—, and G is heterocycloalkyl, C₃-C₇cycloalkyl,        aryl, or heteroaryl.

Each of which (ii), (iii), and (iv) is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- anddi-C₁-C₄alkylcarboxamide, and phenyl.

And, R₁ is substituted with 0 or 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.

R₂ is C₁-C₇ alkyl, (C₁-C₆alkoxy)C₀-C₆alkoxy,(heterocycloalkyl)C₀-C₂alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, or R₂ is(phenyl)C₀-C₂alkyl, (phenoxy)C₀-C₂alkyl, or (heteroaryl)C₀-C₂alkyl, eachof which is substituted with 0 to 3 substituents independently chosenfrom hydroxy, nitro, cyano, amino, halogen, —SO₂NH₂, oxo, —COOH, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₂-C₆alkanoyl,C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆alkyl, mono- anddi-C₁-C₆alkylamino, mono- and di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ isC₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, or heteroaryl.

Z, is

wherein R₄ is hydrogen, or R₄ is C₁-C₆alkyl, C₃-C₇cycloalkyl,heterocycloalkyl, phenyl, or heteroaryl, each of which is substitutedwith 0 or 1 or more substituents independently chosen from hydroxy,nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono- anddi-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is C₁-C₆ alkyl,C₁-C₃haloalkyl, or phenyl.

-   -   Q is phenyl or pyridyl.    -   R₃ is hydrogen, halogen, or C₁-C₇ alkyl, or    -   R₃ is heterocycloalkyl, C₃-C₇cycloalkyl, or heteroaryl, each of        which is substituted with from 0 to 3 substituents independently        chosen from hydroxy, nitro, cyano, amino, halogen, —SO₂NH₂, oxo,        C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,        C₁-C₃halooalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,        (C₁-C₆-alkoxy)C₁-C₆ alkoxy, mono- and di-C₁-C₆alkylamino,        aminoC₁-C₆ alkyl, and —C(O)R₁₄.        The Variable A

Also included herein are compounds of Formula 1 wherein A is 0 andcompounds of Formula 1 wherein A is 1.

The Variable R₁

Further provided herein are compounds of Formula 1 and pharmaceuticallyacceptable forms thereof, wherein the variable R₁ satisfies one or moreof the following conditions set forth in A. to O.

A. R₁ is phenyl or pyridyl, each of which is substituted with one of

-   -   (i) oxo, —CHO, —COOH, —CONH₂, or —CONHOH,    -   (ii) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,        C₁-C₆hydroxyalkoxy, (mono- or di-C₁-C₆alkylamino)C₁-C₆alkoxy,        (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,        (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, heterocycloalkyl, aryl,        or heteroaryl,    -   (iii) —C₁-C₆alkyl(C═O)OR₁₀, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,        —C₁-C₆alkylNR₁₀(SO₂)R₁₁, —C₀-C₆alkylNR₁₀(C═O)R₁₁,        —C₀-C₆alkyl(SO₂)R₁₀, or —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, where R₁₀,        R₁₁, and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,        C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, or heterocycloalkyl, or    -   (iv) -L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or        —(C₁-C₂alkyl)(C═O)—, and G is heterocycloalkyl, C₃-C₇cycloalkyl,        aryl, or heteroaryl.

Each of which (ii), (iii), and (iv) is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- anddi-C₁-C₄alkylcarboxamide, and phenyl.

And, R₁ is substituted with 0 or 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.

B. R₁ is phenyl or pyridyl, each of which is substituted with one ofoxo, —CHO, —COOH, —CONH₂, or —CONHOH, and R₁ is substituted with 0 or 1or more substituents independently chosen from hydroxy, nitro, cyano,amino, —SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl, C₁-C₄haloalkyl,C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl, (C₁-C₆alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆ alkylamino)C₀-C₆ alkyl, andC₁-C₆alkoxycarbonyl.

C. R₁ is phenyl or pyridyl, each of which is substituted with one ofoxo, —CHO, —COOH, —CONH₂, or —CONHOH, and R₁ is substituted with from 0to 3 substituents independently chosen from hydroxy, cyano, halogen,C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxy,and mono- and di-C₁-C₄alkylamino.

D. R₁ is phenyl or pyridyl, each of which is substituted with one ofoxo, —CHO, —COOH, —CONH₂, or —CONHOH, and R₁ is substituted with from 0to 3 substituents independently chosen from hydroxy, cyano, halogen,C₁-C₂alkyl, and C₁-C₂alkoxy.

E. R₁ is phenyl or pyridyl, each of which is substituted with one of(ii) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,C₁-C₆hydroxyalkoxy, (mono- or di-C₁-C₆alkylamino)C₁-C₆alkoxy,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, heterocycloalkyl, aryl, orheteroaryl.

Each of which (ii) is substituted with 0 to 3 substituents independentlychosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono- anddi-C₁-C₄alkylamino, mono- and di-C₁-C₄alkylcarboxamide, and phenyl.

And, R₁ is substituted with 0 or 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.

F. R₁ is phenyl or pyridyl, each of which is substituted with one ofC₁-C₆hydroxyalkyl, C₁-C₆hydroxyalkoxy, (mono- ordi-C₁-C₆alkylamino)C₁-C₆alkoxy,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, or(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, each of which is substituted with0 to 3 substituents independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono- anddi-C₁-C₄alkylamino, and mono- and di-C₁-C₄alkylcarboxamide.

And, R₁ is substituted with from 0 to 3 substituents independentlychosen from hydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxy, and mono- anddi-C₁-C₄alkylamino.

G. R₁ is phenyl or pyridyl, each of which is substituted with one ofC₁-C₆hydroxyalkyl, C₁-C₆hydroxyalkoxy, (mono- ordi-C₁-C₆alkylamino)C₁-C₆alkoxy,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, or(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy.

And, R₁ is substituted with from 0 to 3 substituents independentlychosen from hydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.

H. R₁ is phenyl or pyridyl, each of which is substituted with one ofpyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,[1,4]diazepanyl, phenyl, imidazolyl, or5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, each of which issubstituted with 0 to 3 substituents independently chosen from halogen,hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono- and di-C₁-C₄alkylamino, and mono- and di-C₁-C₄alkylcarboxamide.

And, R₁ is substituted with from 0 to 3 substituents independentlychosen from hydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxy, and mono- anddi-C₁-C₄alkylamino.

I. R₁ is phenyl or pyridyl, each of which is substituted with one ofpyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,[1,4]diazepanyl, phenyl, imidazolyl, or5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, each of which issubstituted with 0 to 3 substituents independently chosen from halogen,hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, and mono- anddi-C₁-C₄alkylcarboxamide.

And, R₁ is substituted with from 0 to 3 substituents independentlychosen from hydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.

J. R₁ is phenyl or pyridyl, each of which is substituted with one of(iii) —C₁-C₆alkyl(C═O)OR₁₀, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,—C₁-C₆alkylNR₁₀(SO₂)R₁, —C₀-C₆alkylNR₁₀(C═O)R₁₁, —C₀-C₆alkyl(SO₂)R₁₀, or—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ where R₁₀, R₁₁, and R₁₂ are independentlyhydrogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₇cycloalkyl, orheterocycloalkyl, Each of which (iii) is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- anddi-C₁-C₄alkylcarboxamide, and phenyl.

And, R₁ is substituted with 0 or 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.

K. R₁ is phenyl or pyridyl, each of which is substituted with one of—C₁-C₄alkyl(C═O)OR₁₀, —C₀-C₄alkyl(C═O)NR₁₀R₁₁, —C₁-C₄alkylNR₁₀(SO₂)R₁₁,—C₀-C₄alkylNR₁₀(C═O)R₁₁, —C₀-C₄alkyl(SO₂)R₁₀, or—C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂ where R₁₀, R₁₁, and R₁₂ are independentlyhydrogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₁₀cycloalkyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, or[1,4]diazepanyl, each of which is substituted with 0 to 3 substituentsindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono- anddi-C₁-C₄alkylamino, and mono- and di-C₁-C₄alkylcarboxamide.

And, R₁ is substituted with from 0 to 3 substituents independentlychosen from hydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.

L. R₁ is phenyl or pyridyl, each of which is substituted with one of(iv) -L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or—(C₁-C₂alkyl)(C═O)—, and G is heterocycloalkyl, C₃-C₇cycloalkyl, aryl,or heteroaryl, each of which (iv) is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- anddi-C₁-C₄alkylcarboxamide, and phenyl.

And, R₁ is substituted with 0 or 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.

M. R₁ is phenyl or pyridyl, each of which is substituted with one of-L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or—(C₁-C₂alkyl)(C═O)—, and G is pyrrolidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidinyl, [1,4]diazepanyl, phenyl,imidazolyl, or 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, each ofwhich is substituted with 0 to 3 substituents independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, and mono- anddi-C₁-C₄alkylcarboxamide.

And, R₁ is substituted with from 0 to 3 substituents independentlychosen from hydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and mono- and di-C₁-C₄alkylamino.

N. R₁ is phenyl or pyridyl, each of which is substituted with one of-L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or—(C₁-C₂alkyl)(C═O)—, and G is pyrrolidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidinyl, [1,4]diazepanyl, phenyl,imidazolyl, or 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, each ofwhich is substituted with 0 to 3 substituents independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, andmono- and di-C₁-C₄alkylcarboxamide.

And, R₁ is substituted with from 0 to 3 substituents independentlychosen from hydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.

O. L is phenyl or pyridyl, each of which is substituted with one of—CH₂—, —(C═O)—, or —(CH₂)(C═O)—, and G is pyrrolidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidinyl, or [1,4]diazepanyl, each ofwhich is substituted with 0 to 3 substituents independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₂alkyl, C₁-C₂alkoxy,C₂-C₂alkanoyl, C₁-C₂alkoxycarbonyl, mono- and di-C₁-C₂alkylamino, andmono- and di-C₁-C₂alkylcarboxamide.

And, R₁ is substituted with from 0 to 3 substituents independentlychosen from hydroxy, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.

Also disclosed herein are compounds and pharmaceutically acceptableforms of Formula 2:

Within Formula 2

A, R₂, Z₁, Q, and R₃ carry any of the definitions set forth herein forthese variables. For example R₂ may have the definition set forth forthis variable in Formula I-a, R₂ may have the definition set forth forthis variable in Formula 1, R₂ may have any of the values set forth forthis variable in the claims, or in the subsection titled “the R₂variable.”

-   -   R is    -   (i) oxo, —CHO, —COOH, —CONH₂, or —CONHOH,    -   (ii) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,        C₁-C₆hydroxyalkoxy, (mono- or di-C₁-C₆alkylamino)C₁-C₆alkoxy,        (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,        (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, heterocycloalkyl, aryl,        or heteroaryl,    -   (iii) —C₁-C₆alkyl(C═O)OR₁₀, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,        —C₁-C₆alkylNR₁₀(SO₂)R₁₁, —C₀-C₆alkylNR₁₀(C═O)R₁₁,        —C₀-C₆alkyl(SO₂)R₁₀, or —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ where R₁₀,        R₁₁, and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,        C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, or heterocycloalkyl, or    -   (iv) -L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or        —(C₁-C₂alkyl)(C═O)—, and G is heterocycloalkyl, C₃-C₇cycloalkyl,        aryl, or heteroaryl, Each of which (ii), (iii), and (iv) is        substituted with 0 to 3 substituents independently chosen from        halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,        C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,        C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,        C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- and        di-C₁-C₄alkylcarboxamide, and phenyl.

R_(A) is 0 or 1 or more substituents independently chosen from hydroxy,nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl,C₁-C₂haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl,(C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆ alkylamino)C₀-C₆ alkyl,and C₁-C₆alkoxycarbonyl.

Another embodiment includes compounds and pharmaceutically acceptableforms in which R₁ is a phenyl substituted at the para position by R, andsubstituted at any other position by R_(A) i.e. the invention providescompounds and pharmaceutically acceptable forms of Formula 3

Within Formula 3

R₂, Z₁, Q, and R₃ carry any of the definitions set forth herein forthese variables and R and R_(A) carry the definitions set forth forthese variables for Formula 2.

The R₂ Variable

Further provided herein are compounds of Formula 1 and pharmaceuticallyacceptable forms thereof, wherein the variable R₂ satisfies one or moreof the following conditions.

A. R₂ is (phenyl)C₀-C₂alkyl, (phenoxy)C₀-C₂alkyl, or(pyridyl)C₀-C₂alkyl, each of which is substituted with 0 to 3substituents independently chosen from hydroxy, nitro, cyano, amino,halogen, —SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono- and di-C₁-C₆ alkylamino, mono- anddi-C₁-C₆alkylcarboxamide, C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and—C═O)R₁₃ wherein R₁₃ is C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl,C₁-C₃haloalkyl, heterocycloalkyl, phenyl, or heteroaryl.

B. R₂ is (phenyl)C₀-C₂alkyl, (phenoxy)C₀-C₂alkyl, or(pyridyl)C₀-C₂alkyl, each of which is substituted with 0 to 3substituents independently chosen from hydroxy, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄alkanoyl,C₁-C₄hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono- anddi-C₁-C₆alkylamino, mono- and di-C₁-C₆alkylcarboxamide,C₁-C₄alkoxycarbonyl, phenyl, and imidazolyl.

The Z₁ Variable

Within certain embodiments Z₁ is

wherein R₄ is hydrogen, C₁-C₆alkyl, or C₃-C₇cycloalkyl, In some of theseembodiments R₄ is hydrogen or methyl.The Q Variable

Additional embodiments, pertain to compounds and pharmaceuticallyacceptable forms of Formula 4 and Formula 5

Within Formula 4 and 5:

-   -   A, R. R_(A), R₁, R₂, Z₁, and R₃ carry any of the definitions set        forth herein for these variables.

In certain embodiments of Formula 5, R is

-   -   (i) oxo, —CHO, —COOH, —CONH₂, or —CONHOH,    -   (ii) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,        C₁-C₆hydroxyalkoxy, (mono- or di-C₁-C₆alkylamino)C₁-C₆alkoxy,        (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,        (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, heterocycloalkyl, aryl,        or heteroaryl,    -   (iii) —C₁-C₆alkyl(C═O)OR₁₀, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,        —C₁-C₆alkylNR₁₀(SO₂)R₁, —C₀-C₆alkylNR₁₀(C═O)R₁₁,        —C₀-C₆alkyl(SO₂)R₁₀, or —C₀-C₆alkylNR₀(C═O)NR₁₁R₁₂ where R₁₀,        R₁₁, and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,        C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, or heterocycloalkyl, or    -   (iv) -L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or        —(C₁-C₂alkyl)(C═O)—, and G is heterocycloalkyl, C₃-C₇cycloalkyl,        aryl, or heteroaryl.

Each of which (ii), (iii), and (iv) is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- anddi-C₁-C₄alkylcarboxamide, and phenyl.

R_(A) is 0 or 1 or more substituents independently chosen from hydroxy,nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl,(C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆ alkylamino)C₀-C₆ alkyl,and C₁-C₆alkoxycarbonyl.

The R₃ Variable

R₃ is hydrogen or methyl in certain compounds of the invention andpharmaceutically acceptable forms described herein.

Additional embodiments of the invention pertain to compounds of Formula6

and the pharmaceutically acceptable forms thereof.

-   -   Within Formula 6    -   Z₁, R₃ and A variables carry any of the definitions set forth        herein for these variables.    -   R₁ is phenyl or heteroaryl, each of which is optionally        substituted with one of    -   (i) oxo, —CHO, —COOH, —CONH₂, or —CONHOH,    -   (ii) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,        C₁-C₆hydroxyalkoxy, (mono- or di-C₁-C₆alkylamino)C₁-C₆alkoxy,        (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,        (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, heterocycloalkyl, aryl,        or heteroaryl,    -   (iii) —C₁-C₆alkyl(C═O)OR₁₀, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,        —C₁-C₆alkylNR₁₀(SO₂)R₁₁, —C₀-C₆alkylNR₁₀(C═O)R₁₁,        —C₀-C₆alkyl(SO₂)R₁₀, or —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ where R₁₀,        R₁₁, and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,        C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, or heterocycloalkyl, or    -   (iv) -L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or        —(C₁-C₂alkyl)(C═O)—, and G is heterocycloalkyl, C₃-C₇cycloalkyl,        aryl, or heteroaryl.

Each of which (ii), (iii), and (iv) is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- anddi-C₁-C₄alkylcarboxamide, and phenyl.

And, R₁ is substituted with 0 or 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.

R₅ is isopropyl or t-butyl.

Other embodiments pertain to compounds and forms thereof of Formula 7 toFormula 9

Within Formula 7 to Formula 9:

-   -   R is    -   (i) oxo, —CHO, —COOH, —CONH₂, or —CONHOH,    -   (ii) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,        C₁-C₆hydroxyalkoxy, (mono- or di-C₁-C₆alkylamino)C₁-C₆alkoxy,        (C₁-C₆alkoxy) (C₁-C₆alkylamino)C₀-C₆alkyl,        (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, heterocycloalkyl, aryl,        or heteroaryl,    -   (iii) —C₁-C₆alkyl(C═O)OR₁₀, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,        —C₁-C₆alkylNR₁₀(SO₂)R₁₁, —C₀-C₆alkylNR₁₀(C═O)R₁₁,        —C₀-C₆alkyl(SO₂)R₁₀, or —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ where R₁₀,        R₁₁, and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,        C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, or heterocycloalkyl, or    -   (iv) -L-G, where L is C₁-C₂alkyl, C₀-C₂alkoxy, —(C═O)—, or        —(C₁-C₂alkyl)(C═O)—, and G is heterocycloalkyl, C₃-C₇cycloalkyl,        aryl, or heteroaryl.

Each of which (ii), (iii), and (iv) is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono- and di-C₁-C₄alkylamino, mono- anddi-C₁-C₄alkylcarboxamide, and phenyl.

R_(A) is 0 or 1 or more substituents independently chosen from hydroxy,nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl,(C₁-C₆ alkoxy)C₀-C₆alkyl, (mono- and di-C₁-C₆ alkylamino)C₀-C₆ alkyl,and C₁-C₆alkoxycarbonyl.

R₅ is isopropyl or t-butyl.

A, Z₁, and R₃ may carry any of the definitions set forth above for thesevariables. It certain embodiments it is preferred that R₃ is hydrogen ormethyl.

Pharmaceutical Preparations

Compounds, salts, and any other pharmaceutically acceptable forms of theinvention can be administered as the neat chemical, but are preferablyadministered as a pharmaceutical composition or formulation.Accordingly, the invention provides pharmaceutical formulationscomprising a compound or pharmaceutically acceptable form of FormulaI-a, together with one or more pharmaceutically acceptable carriers,excipients, adjuvants, diluents, or other ingredients.

Pharmaceutical carriers must be of sufficiently high purity andsufficiently low toxicity to render them suitable for administration tothe animal being treated. The carrier can be inert or it can possesspharmaceutical benefits. The amount of carrier employed in conjunctionwith the compound is sufficient to provide a practical quantity ofmaterial for administration per unit dose of the compound.

Exemplary pharmaceutically acceptable carriers or components thereof aresugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; synthetic oils; vegetable oils,such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil;polyols such as propylene glycol, glycerine, sorbitol, mannitol, andpolyethylene glycol; alginic acid; phosphate buffer solutions;emulsifiers, such as the TWEENS; wetting agents, such sodium laurylsulfate; coloring agents; flavoring agents; tableting agents;stabilizers; antioxidants; preservatives; pyrogen-free water; isotonicsaline; and phosphate buffer solutions.

Optional active agents may be included in a pharmaceutical composition,which do not substantially interfere with the activity of the compoundof the present invention.

Effective concentrations of one or more of the compounds of theinvention including pharmaceutically acceptable salts, esters or otherderivatives thereof are mixed with a suitable pharmaceutical carrier,excipients, adjuvant, or vehicle. In instances in which the compoundsexhibit insufficient solubility, methods for solubilizing compounds maybe used. Such methods are known to those of skill in this art, andinclude, but are not limited to, using cosolvents, such asdimethylsulfoxide (DMSO), using surfactants, such as TWEEN, ordissolution in aqueous sodium bicarbonate. Derivatives of the compounds,such as salts of the compounds or prodrugs of the compounds may also beused in formulating effective pharmaceutical compositions.

Upon mixing or addition of the compound(s) of the invention, theresulting mixture may be a solution, suspension, emulsion or the like.The form of the resulting mixture depends upon a number of factors,including the intended mode of administration and the solubility of thecompound in the chosen carrier or vehicle. The effective concentrationsufficient for ameliorating the symptoms of the disease treated and maybe empirically determined.

Compounds of provided herein may be administered orally, topically,parenterally, intravenously, by intramuscular injection, by inhalationor spray, sublingually, transdermally, via buccal administration,rectally, as an ophthalmic solution, or by other means, in dosage unitformulations.

Dosage formulations suitable for oral use, include, for example,tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agents, suchas sweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide pharmaceutically elegant and palatablepreparations. Oral formulations contain between 0.1 and 99% of acompound of the invention and usually at least about 5% (weight %) of acompound of the present invention. Some embodiments contain from about25% to about 50% or from 5% to 75% of a compound of invention.

Orally administered compositions also include liquid solutions,emulsions, suspensions, powders, granules, elixirs, tinctures, syrups,and the like. The pharmaceutically acceptable carriers suitable forpreparation of such compositions are well known in the art. Oralformulations may contain preservatives, flavoring agents, sweeteningagents, such as sucrose or saccharin, taste-masking agents, and coloringagents.

Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol or sucrose. Such formulations may also contain ademulcent.

Orally Administered Liquids Formulations

Compounds of the invention can be incorporated into oral liquidpreparations such as aqueous or oily suspensions, solutions, emulsions,syrups, or elixirs, for example. Moreover, formulations containing thesecompounds can be presented as a dry product for constitution with wateror other suitable vehicle before use. Such liquid preparations cancontain conventional additives, such as suspending agents (e.g.,sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin,hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel,and hydrogenated edible fats), emulsifying agents (e.g., lecithin,sorbitan monsoleate, or acacia), non-aqueous vehicles, which can includeedible oils (e.g., almond oil, fractionated coconut oil, silyl esters,propylene glycol and ethyl alcohol), and preservatives (e.g., methyl orpropyl p-hydroxybenzoate and sorbic acid).

Suspensions

For a suspension, typical suspending agents include methylcellulose,sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80;and typical preservatives include methyl paraben and sodium benzoate.

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents; may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example peanut oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Emulsions

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or peanut oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate.

Dispersible Powders

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

Tablets and Capsules

Tablets typically comprise conventional pharmaceutically compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components oftendepends on secondary considerations like taste, cost, and shelfstability.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Injectable and Parenteral Formulations

Pharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents that have been mentioned above. The sterileinjectable preparation may also be sterile injectable solution orsuspension in a non-toxic parentally acceptable diluent or solvent, forexample as a solution in 1,3-butanediol. Among the acceptable vehiclesand solvents that may be employed are water, Ringer's solution, andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are useful inthe preparation of injectables.

Compounds of the invention may be administered parenterally in a sterilemedium. Parenteral administration includes subcutaneous injections,intravenous, intramuscular, intrathecal injection or infusiontechniques. The compound or compounds of the invention, depending on thevehicle and concentration used, can either be suspended or dissolved inthe vehicle. Advantageously, adjuvants such as local anesthetics,preservatives and buffering agents can be dissolved in the vehicle. Inmany compositions for parenteral administration the carrier comprises atleast about 90% by weight of the total composition. Preferred carriersfor parenteral administration include propylene glycol, ethyl oleate,pyrrolidone, ethanol, and sesame oil.

Suppositories

Compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient that is solid at ordinary temperatures but liquid at rectaltemperature and will therefore melt in the rectum to release the drug.Such materials include cocoa butter and polyethylene glycols.

Topical Formulations

Compounds of the invention may be formulated for local or topicalapplication, such as for topical application to the skin and mucousmembranes, such as in the eye, in the form of gels, creams, and lotionsand for application to the eye. Topical compositions of the presentinvention may be in any form including, for example, solutions, creams,ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skinpatches, and the like.

Such solutions may be formulated as 0.01%-10% isotonic solutions, pHabout 5-7, with appropriate salts. Compounds of the invention may alsobe formulated for transdermal administration as a transdermal patch.

Topical compositions containing the active compound can be admixed witha variety of carrier materials well known in the art, such as, forexample, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin Aand E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate,and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows:

Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glycerylmonostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetylalcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate,isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate,decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate,iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethyleneglycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachisoil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil,butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate,lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate;propellants, such as propane, butane, iso-butane, dimethyl ether, carbondioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylenechloride, iso-propanol, castor oil, ethylene glycol monoethyl ether,diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,dimethyl sulphoxide, dimethyl formamide, tetrahydro furan; humectants,such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, solublecollagen, dibutyl phthalate, and gelatin; and powders, such as chalk,talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide,sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl arylammonium smectites, chemically modified magnesium aluminium silicate,organically modified montmorillonite clay, hydrated aluminium silicate,filmed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, andethylene glycol monostearate.

Compounds of the invention may also be topically administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Other Formulations

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol, and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropylmethylcellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions for inhalation typically can be provided in the form of asolution, suspension or emulsion that can be administered as a drypowder or in the form of an aerosol using a conventional propellant(e.g., dichlorodifluoromethane or trichlorofluoromethane).

Additional Components

The compositions of the present invention may also optionally comprisean activity enhancer. The activity enhancer can be chosen from a widevariety of molecules that function in different ways to enhancetherapeutic effects of compounds of the invention. Particular classes ofactivity enhancers include skin penetration enhancers and absorptionenhancers.

Pharmaceutical compositions of the invention may also contain additionalactive agents can be chosen from a wide variety of molecules, which canfunction in different ways to enhance the therapeutic effects of acompound of the invention. These optional other active agents, whenpresent, are typically employed in the compositions of the invention ata level ranging from about 0.01% to about 15%. Some embodiments containfrom about 0.1% to about 10% by weight of the composition. Otherembodiments contain from about 0.5% to about 5% by weight of thecomposition.

Packaged Formulations

The invention includes packaged pharmaceutical formulations. Suchpackaged formulations include a pharmaceutical composition containingone or more compounds, salts, or other pharmaceutically acceptable formsthereof, of the invention in a container and instructions for using thecomposition to treat a mammal (typically a human patient). Preferablythe instructions are for using the pharmaceutical composition to treat apatient suffering from a disease responsive to inhibition of Btkactivity and/or inhibition of B-cell proliferation. The inventionincludes providing prescribing information; for example, to a patient orhealth care provider, or as a label in a packaged pharmaceuticalformulation. Prescribing information may include for example efficacy,dosage and administration, contraindication and adverse reactioninformation pertaining to the pharmaceutical formulation.

In all of the foregoing the compounds of the invention can beadministered alone, as mixtures, or in combination with other activeagents.

Methods of Treatment

Imidazo[1,2-a]pyrazines active as kinase inhibitors, in particular Btkinhibitors are described herein. These inhibitors are useful fortreating diseases responsive to kinase inhibition, including diseasesresponsive to Btk inhibition and/or inhibition of B-cell proliferation,in mammals. Without wishing to be bound to any particular theory, it isbelieved that the interaction of the compounds of Formula I-a with Btkresults in the inhibition of Btk activity and thus in the pharmaceuticalutility of these compounds. Other kinases that may be affected inaddition to Btk include, but are not limited to, other tyrosine kinasesand serine/threonine kinases.

Accordingly, the invention includes a method of treating a mammal,preferably a human, having a disease responsive to inhibition of Btkactivity, comprising administrating to the mammal having such a disease,an effective amount of a compound of Formula I-a.

To the extent that Btk is implicated in any of the following,alleviation of the disease, disease symptoms, preventative, andprophylactic treatment is within the scope of this invention. Inaddition, as noted above, the compounds of Formula I-a may also inhibitother kinases, such that alleviation of disease, disease symptoms,preventative, and prophylactic treatment of conditions associated withthese kinases is also within the scope of this invention.

Methods of treatment also include inhibiting Btk activity and/orinhibiting B-cell proliferation, by inhibiting ATP binding or hydrolysisby Btk or by some other mechanism, in vivo, in a patient suffering froma disease responsive to inhibition of Btk activity, by administering aneffective concentration of a compound of Formula I-a to inhibit Btkactivity in vitro. An effective concentration may be ascertainedexperimentally, for example by assaying blood concentration of thecompound, or theoretically, by calculating bioavailability.

Diseases Responsive to Kinase Inhibition

Certain compounds described herein are useful for treating a patientsuffering from a disease responsive to kinase inhibition.

Protein kinases, the largest family of human enzymes, are now consideredto be the largest druggable target class. Encompassing well over 500proteins (2% of the human genome), kinases play critical roles insignaling pathways controlling fundamental cellular processes such asproliferation, differentiation, and death (apoptosis). Abnormal kinaseactivity has been implicated in a wide range of diseases, includingmultiple cancers, autoimmune and/or inflammatory diseases, and acuteinflammatory reactions. The multifaceted role of kinases in key cellsignaling pathways provides a significant opportunity to identify noveldrugs targeting kinases and signaling pathways.

Diseases Responsive to Btk Inhibition

The invention includes a method of treating a patient having cancer, anautoimmune and/or inflammatory disease, or an acute inflammatoryreaction, by administering an effective amount of a compound of FormulaI-a.

In a preferred embodiment, the condition responsive to inhibition of Btkactivity and/or B-cell proliferation is cancer, an autoimmune and/orinflammatory disease, or an acute inflammatory reaction.

Preferably, the conditions, diseases that can be affected usingcompounds and compositions according to the invention include, but arenot limited to:

autoimmune and/or inflammatory diseases, including but not limited topsoriasis, allergy, Crohn's disease, irritable bowel syndrome, Sjogren'sdisease, tissue graft rejection, and hyperacute rejection oftransplanted organs, asthma, systemic lupus erythematosus (andassociated glomerulonephritis), dermatomyositis, multiple sclerosis,scleroderma, vasculitis (ANCA-associated and other vasculitides),autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome(and associated glomerulonephritis and pulmonary hemorrhage),atherosclerosis, rheumatoid arthritis, chronic Idiopathicthrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease,Alzheimer's disease, diabetes, septic shock, myasthenia gravis, and thelike,

acute inflammatory reactions, including but not limited to skin sunburn,inflammatory pelvic disease, inflammatory bowel disease, urethritis,uvitis, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, and cholocystitis,and

cancer, including but not limited to, B-cell lymphoma, lymphoma(including Hodgkin's and non-Hodgkins lymphoma), hairy cell leukemia,multiple myeloma, chronic and acute myelogenous leukemia, and chronicand acute lymphocytic leukemia.

Btk is a known inhibitor of apoptosis in lymphoma B-cells. Defectiveapoptosis contributes to the pathogenesis and drug resistance of humanleukemias and lymphomas. Thus, a method of promoting or inducingapoptosis in cells expressing Btk comprising contacting the cell with anagent that inhibits Btk activity is also provided herein.

Combination Therapy

The invention provides methods of treatment in which a compound of theinvention is the only active agent given to a patient and also includesmethods of treatment in which a compound of Formula I-a is given to apatient in combination with one or more additional active agent. Thus inone embodiment the invention provides a method of treating cancer, anautoimmune and/or inflammatory disease, or an acute inflammatoryreaction, which comprises administering to a mammal in need thereof aneffective amount of a compound of Formula I-a together with a secondactive agent, which is useful for treating an cancer, an autoimmuneand/or inflammatory disease, or an acute inflammatory reaction. Forexample the second agent may be an anti-inflammatory agent. Treatmentwith the second active agent may be prior to, concomitant with, orfollowing treatment with a compound of Formula I-a. In certainembodiments a compound of Formula I-a is combined with another activeagent in a single dosage form. Suitable antitumor therapeutics that maybe used in combination with a compound of Formula I-a include, but arenot limited to chemotherapeutic agents, for example mitomycin C,carboplatin, taxol, cisplatin, paclitaxel, etoposide, doxorubicin, or acombination comprising at least one of the foregoing chemotherapeuticagents. Radiotherapeutic antitumor agents may also be used, alone or incombination with chemotherapeutic agents.

Btk inhibitors are useful as chemosensitizing agents, and, thus, areuseful in combination with other chemotherapeutic drugs, in particular,drugs that induce apoptosis.

A method for increasing sensitivity of cancer cells to chemotherapy,comprising administering to a patient undergoing chemotherapy achemotherapeutic agent together with a Btk inhibitor in an amountsufficient to increase the sensitivity of cancer cells to thechemotherapeutic agent is also provided herein.

Examples of other chemotherapeutic drugs that can be used in combinationwith Btk inhibitors include topoisomerase I inhibitors (camptothesin ortopotecan), topoisomerase II inhibitors (e.g. daunomycin and etoposide),alkylating agents (e.g. cyclophosphamide, melphalan and BCNU), tubulindirected agents (e.g. taxol and vinblastine), and biological agents(e.g. antibodies such as anti CD20 antibody, IDEC 8, immunotoxins, andcytokines).

Included herein are methods of treatment in which a compound of FormulaI-a in administered in combination with an anti-inflammatory agent.Anti-inflammatory agents include but are not limited to NSAIDs,non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, goldcompounds, corticosteroids, methotrexate, tumor necrosis factor receptor(TNF) receptors antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, and prednisone.

In additional embodiments the anti-inflammatory agent is therapeuticagent is a gold compound such as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-C5 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asmethotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, ormycophenolate mofetil.

Dosage Levels

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most autoimmuneand/or inflammatory, a dosage regimen of 4 times daily or less ispreferred and a dosage regimen of 1 or 2 times daily is particularlypreferred.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the patient undergoing therapy.

EXAMPLES Example 1 EXEMPLARY SYNTHESIS OF CERTAINIMIDAZO[1,2-A]PYRAZIN-8-YLAMINES

Step 1. 6,8-dibromoimidazo[1,2-a]pyrazine (3)

A mixture of bromoacetaldehyde diethyl acetal (51 grams (g)), 48%hydrobromic acid (HBr) (11 milliliters (mL)), and water (11 mL) isheated at 120° C. for 1 hour (hr). The solution is cooled, poured into amixture of sodium bicarbonate (NaHCO₃) (60 g) and isopropyl alcohol(IPA) (200 mL), and stirred for 0.5 hr. The mixture is filtered, and thefiltrate is treated with 3,5-dibromo-2-aminopyrazine (1) (33 g) andheated under reflux for 16 hr. The suspension is cooled in ice, treatedwith 48% HBr (3 mL) and diethyl ether (60 mL) and filtered to afford (3)as the hydrobromide salt.Step 2. (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-phenyl-amine (4)

Tri-o-tolylphosphine (1.1 g) is added to a suspension oftris(dibenzylideneacetone)dipalladium (1.65 g) in degassed toluene (50mL) and the mixture is stirred at room temperature for 15 minutes (min).6,8-Dibromo-imidazo[1,2-a]pyrazine (5.0 g) is then added and the mixtureis stirred at room temperature for 15 minutes more. Aniline (1.52 g) isadded followed by potassium t-butoxide (2.84 g) and the mixture isstirred at room temperature for 72 hr. Water (150 mL) is added and themixture is extracted with ethyl acetate (3×150 mL), the extracts arewashed with water (1×100 mL) and brine (1×100 mL), dried over MgSO₄, andevaporated in vacuo to afford a gum. Trituration with diethyl etheraffords (6-bromo-imidazo[1,2-a]pyrazin-8-yl)-phenyl-amine (4) as a brownsolid.Step 3-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-phenyl-amine (5)

A mixture of (6-bromo-imidazo[1,2-a]pyrazin-8-yl)-phenyl-amine (4) (1.9g), 3-aminophenylboronic acid hemisulfate (1.35 g),tetrakis(triphenylphosphine) palladium (380 mg), 1M aqueous sodiumcarbonate (20 mL), and 1,2-dimethoxyethane (40 mL) is heated at 90° for16 hr. The mixture is cooled to room temperature, treated with water (50mL) and extracted with ethyl acetate (3×80 mL). The extracts are washedwith water (1×50 mL) and brine (1×50 mL), dried over MgSO₄, andevaporated in vacuo to afford a gum which is purified by flashchromatography over silica gel, eluting with ethyl acetate, to afford[6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-phenyl-amine (5) as alight brown solid.Step 4.4-tert-Butyl-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide(6)

A solution of[6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-phenyl-amine (5) (50mg), 4-tert-butyl-benzoyl chloride (0.83 mL of a 0.2M solution intoluene), and triethylamine (0.034 mL) in toluene (1 mL) andN,N,-dimethylformamide (1 mL) is stirred at room temperature for 16 hr.The mixture is purified by preparative thin layer chromatography oversilica gel, eluting with diethyl ether/dichloromethane (1:1) to afford4-tert-butyl-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide(6) as a cream foam.

Example 2 SYNTHESIS OFN-(4-TERT-BUTYL-PHENYL)-3-{8-[4-(MORPHOLIN-4-CARBONYL)-PHENYLAMINO]-IMIDAZO[1,2-A]PYRAZIN-6-YL}-BENZAMIDE

Step. 1. 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic Acid (7)

A mixture of 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acidethyl ester (30 mmol), 1N aqueous sodium hydroxide (50 mL), and ethanol(80 mL) is heated at reflux for 1.5 hr. The mixture is cooled and theethanol removed in vacuo. The residue is diluted with iN sodiumhydroxide (30 mL) and washed with ethyl acetate (2×100 mL). The aqueouslayer is brought to pH 6 with 3N HCl, and the mixture filtered to give4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (7) as a lightorange solid.Step 2.[4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone(8)

A mixture of 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid(7) (0.16 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate (0.16 mmol), and N′N-diisopropylethylamine (0.48mmol) is stirred at room temperature for 20 min. under N₂. Morpholine(0.48 mmol) is added and the mixture is stirred at room temperature for16 hr. Water (10 mL) is added and the mixture extracted with ethylacetate (2×70 mL). The extracts are subsequently washed with water (2×30mL) and brine (1×30 mL), dried over sodium sulfate, and concentrated invacuo. The residue is triturated with diethyl ether to give[4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone(8) as a cream solid.Step 3.3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzoicacid (9)

The bromide (8) (2,46 mmol) is dissolved in 10 mL DME (ethylene glycol,dimethyl ether) in a sealable pressure vessel and N₂ is bubbled throughfor 10 min. Tetrakis(triphenylphosphine)palladium (0.24 mmol) is addedand N₂ is bubbled through the reaction for another 10 minutes.3-Carboxyphenyl boronic acid (3.1 mmol) and IN Na₂CO₃ solution (10 mL)are then added, the vessel sealed, and the reaction heated to 95° C. for16 hrs. with vigorous stirring. After cooling to room temperature, thereaction is acidified to pH 3 with iN HCl and extracted with ethylacetate (3×25 mL). The pooled ethyl acetate layers are washed withbrine, dried over sodium sulfate, and the solvent removed in vacuo. Theresulting solid is then dissolved in a minimal volume of CH₂Cl₂ andprecipitated out as a whitish-tan solid by slow addition of ethylacetate (5 mL) followed by hexanes (30 mL) to yield3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzoicacid (9).Step 4.N-(4-tert-Butyl-phenyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzamide(10)

A mixture of3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzoicacid (9) (0.23 mmol),benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphatereagent (0.23 mmol) and N,N′-diisopropylethylamine (0.77 mmol) isstirred under N₂ for 15 min. in 1 mL DMF. 4-tert-Butyl-phenylamine (0.37mmol) is added and the reaction stirred at rt for 8 hrs. The reaction ispartitioned between ethyl acetate (15 mL) and water (15 mL) and theethyl acetate layer washed with water (2×15 mL) and brine (1×15 mL). Theorganic layer is dried over sodium sulfate and the solvent removed invacuo. The resulting crude oil is dissolved in 1 ml CH₂Cl₂ and cleanyellow solid is precipitated by slow addition of diethyl ether, yieldingthe final product, (10)N-(4-tert-Butyl-phenyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzamide.

Example 3 SYNTHESIS OFN-(3-{8-[4-(4-ACETYL-PIPERAZIN-1-YL)-PHENYLAMINO]-IMIDAZO[1,2-A]PYRAZIN-6-YL}-PHENYL)-4-TERT-BUTYL-BENZAMIDE

Step 1. 4-(4-Nitro-phenyl)-piperazine-1-carboxylic Acid Tert-Butyl Ester

A mixture of 1-fluoro-4-nitrobenzene (20.4 mmol),piperazine-1-carboxylic acid tert-butyl ester (20.4 mmol), potassiumcarbonate (40.8 mmol), and N′N-dimethylformamide (80 mL) is heated at60° C. for 3 hrs. The mixture is cooled to room temperature, treatedwith water (100 mL), extracted with ethyl acetate (3×80 mL). Theextracts are washed with water (3×60 mL) and brine (1×75 ml), dried overmagnesium sulfate, and concentrated in vacuo to give4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (11) asa yellow solid.Step 2. 4-(4-Amino-phenyl)-piperazine-1-carboxylic Acid Tert-Butyl Ester

A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butylester (11) (18.9 mmol), 10% palladium-on-carbon (600 mg), ethanol (100mL), and ethyl acetate (100 mL) is hydrogenated at room temperature and40 psi for 2 hrs. The mixture is filtered through celite, washing withethyl acetate (2×100 mL), and concentrated in vacuo to give4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (12) asa brown oil.Step 3.4-[4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-piperazine-1-carboxylicAcid Tert-Butyl Ester

A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (12.5 mmol),4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (12)(13.1 mmol), potassium carbonate (25 mmol), acetonitrile (50 mL) andN,N-dimethylacetamide (20 mL) is heated at 65° C. for 16 hrs. Themixture is cooled to room temperature, treated water (100 mL), andextracted with ethyl acetate (3×80 mL). The extracts are washed withwater (3×60 mL) and brine (1×60 mL), dried over magnesium sulfate, andconcentrated in vacuo. The residue is chromatographed over silica gel,eluting with ethyl acetate, to give4-[4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester (13) as a light brown foam.Step 4.4-{4-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylicAcid Tert-Butyl Ester (14)

A mixture of 4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acidethyl ester (13) (4,33 mmol), 3-aminophenylboronic acid hemisulfate(5,63 mmol), tetrakis(triphenylphosphine)palladium (0.2 mmol), 1Naqueous sodium carbonate solution (13 mL), and dimethoxyethane (70 mL)is heated at 95° C. for 2 days. The mixture is allowed to cool, treatedwith water (100 mL), and extracted with ethyl acetate (3×80 mL). Theextracts are washed with water (2×75 mL) and brine (1×75 mL), dried overmagnesium sulfate, and evaporated in vacuo. The residue ischromatographed over silica gel, eluting with ethyl acetate, to give4-{4-[6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (14) as a cream solid.Step 5.4-(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-piperazine-1-carboxylicAcid Tert-Butyl Ester (15)

An ice-cold solution of4-{4-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (14) (2.35 mmol), triethylamine (3.53 mmol), andtetrahydrofuran (20 mL) is treated dropwise with a solution of4-t-butylbenzoyl chloride (2.35 mmol) in tetrahydrofuran (10 mL). Themixture is stirred at room temperature for 1 hr. Water (50 mL) is addedand the mixture extracted with ethyl acetate (3×70 mL). The extracts arewashed with water (2×50 mL) and brine (1×50 mL), dried over magnesiumsulfate, and evaporated in vacuo. The residue is triturated with diethylether to give4-(4-{6-[3-(4-tert-butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (15) as a cream solid.Step 6.4-tert-Butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide(16)

A mixture of4-(4-{6-[3-(4-tert-butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (15) (2.0 mmol), 1M HCl in diethyl ether (20 mL),and dioxane (60 mL) is stirred at room temperature for 16 hr. Water (100mL) is added and the pH brought to 11 with 1N NaOH. The mixture isextracted with ethyl acetate (3×80 mL), the extracts washed with water(2×70 mL) and brine (1×70 mL), dried over magnesium sulfate, andconcentrated in vacuo. The residue is slurried with diethyl ether andfiltered to give4-tert-butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide(16) as a cream solid.Step 7.N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-tert-butyl-benzamide(17)

A mixture of4-tert-butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide(16) (0.55 mmol), triethylamine (1.1 mmol), acetic anhydride (0.60mmol), and dichloromethane (10 mL) is stirred at room temperature for 1hr. Water (30 mL) is added, the mixture extracted with dichloromethane(2×50 mL), the extracts washed with water (2×30 mL) and brine (1×30 mL),dried over magnesium sulfate, and concentrated in vacuo. The residue istriturated with diethyl ether and ethyl acetate to giveN-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-tert-butyl-benzamide(17) as a cream solid.

Example 4 SYNTHESIS OF4-TERT-BUTYL-N-(3-{8-[4-(MORPHOLINE-4-CARBONYL)-PHENYLAMINO]-IMIDAZO[1,2-A]PYRAZIN-6-YL}-PHENYL)-BENZAMIDE

Step 1. 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic Acid EthylEster (18)

A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (0.18 mol),4-aminobenzoic acid ethyl ester (2) (0.18 mol), andN,N-dimethylacetamide (30 mL) is heated at 160° C. for 30 min. Themixture is cooled to room temperature, treated with ethyl acetate (150mL), stirred, and filtered to afford an orange/brown solid. This solidis slurried with ethyl acetate and saturated sodium bicarbonate solutionto give 4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethylester (18) freebase.Step 2. 4-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzoicAcid Ethyl Ester (19)

A mixture of 4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acidethyl ester (18) (55.3 mmol), 3-aminophenylboronic acid hemisulfate (72mmol), tetrakis(triphenylphosphine)palladium (2.8 mmol), 1N aqueoussodium carbonate solution (166 mmol), and dimethoxyethane (200 mL) isheated at reflux for 4 days. The mixture is allowed to cool, treatedwith water (200 mL), and extracted with ethyl acetate (4×100 mL). Theextracts are washed with water (2×150 mL) and brine (1×100 mL), driedover magnesium sulfate, and evaporated in vacuo. The residue istriturated with dichloromethane and diethyl ether to give4-[6-(3-aminophenyl)imidazo[1,2-a]pyrazin-8-ylamino]benzoic acid ethylester (19) as a yellow solid.Step 3.4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicAcid Ethyl Ester (20)

An ice-cold solution of4-[6-(3-aminophenyl)imidazo[1,2-a]pyrazin-8-ylamino]benzoic acid ethylester (19) (44.2 mmol), triethylamine (66.4 mmol), and tetrahydrofuran(140 mL) is treated dropwise with a solution of 4-t-butylbenzoylchloride (44.2 mmol) in tetrahydrofuran (60 mL) and the mixture isstirred at room temperature for 1 hr. Water (100 mL) is added and themixture extracted with ethyl acetate (3×100 mL), the extracts are washedwith water (2×100 mL) and brine (1×100 mL), dried over magnesium sulfateand evaporated in vacuo. The residue is triturated with dichloromethaneto give4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoicacid ethyl ester (20) as a pale orange solid.Step 4.4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicAcid (21)

A mixture of4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoicacid ethyl ester (20) (30 mmol), 1N aqueous sodium hydroxide (50 mL),and ethanol (80 mL) is heated at reflux for 1.5 hrs. The mixture iscooled and the ethanol removed in vacuo. The residue is diluted with 1Nsodium hydroxide (30 mL) and washed with ethyl acetate (2×100 mL). Theaqueous layer is brought to pH 6 with 3 N HCl, and the mixture isfiltered to give4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoicacid (21) as a cream solid.Step 5.4-tert-Butyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide(22)

A mixture of4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoicacid (21) (0.16 mmol),benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate(0.16 mmol), and N′N-diisopropylethylamine (0.48 mmol) is stirred atroom temperature for 20 min. Morpholine (0.48 mmol) is added and themixture is stirred at room temperature or 16 hrs. Water (10 mL) is addedand the mixture extracted with ethyl acetate (2×70 mL), the extracts arewashed with water (2×30 mL) and brine (1×30 mL), dried over magnesiumsulfate, and concentrated in vacuo. The residue is triturated withdiethyl ether to give4-tert-B\butyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]imidazo[1,2-a]pyrazin-6-yl}-phenyl)benzamide(22) as a cream solid.

Example 5 ADDITIONAL IMIDAZO[1,2-A]PYRAZIN-8-YLAMINES

The following compounds are synthesized via the procedure set forth inExamples 1 to 4. In some instances changes in starting materials andreaction conditions that will be readily apparent to those skilled inthe art of organic synthesis may be required.

LC-MS data reported in this example is obtained as follows:

LC conditions: RP-HPLC is performed on an AGILENT 1100 Binary HPLCsystem. The column is a Restek Ultra IBD 5 μm 1.0×30 mm (Cat. #:9175331). The Mobile Phase contains component A, 0.2% FormicAcid/Water), and component B, Acetonitrile. The following Gradient isused: Flow Rate Time (min.) % B (μl/min) 0 10 500 1.8 60 500 2.0 95 5002.2 95 500 2.4 10 500

MS conditions: Electrospray MS is performed on a MICROMASS LCT equippedwith a LockSpray source for accurate mass measurements. Spectra areacquired in positive ion mode from 100-1000 Da at an acquisition rate of1 spectrum/0.9 s with a 0.1 s interscan delay. The instrument is tunedfor a resolution of 5000 (FWHM). Every 5^(th) scan is taken from thereference position of the Lockspray source. Leucine enkephalin (556.2771[M+H]⁺) is used as the reference, or lock mass. TABLE I Cmp. Name and MS# Structure Molecular Formula MW m/z (M⁺ 1) 23

4-tert-Butyl-N-[3-(8- phenylamino- imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide MF = C₂₉H₂₇N₅O 461.22 462.21 24

4-Isopropyl-N-[3-(8- phenylamino- imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide MF = C₂₈H₂₅N₅O 447.21 448.21 25

4-tert-Butyl-N-{3-[8- (pyridin-3-ylamino)- imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide MF = C₂₈H₂₆N₆O 462.21 463.07 26

4-tert-Butyl-N-{3-[8- (4-methoxy-phenylamino)- imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide MF = C₃₀H₂₉N₅O₂ 491.23 492.10 27

4-tert-Butyl-N-{3-[8- (pyridin-4-ylamino)- imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide MF = C₂₈H₂₆N₆O 462.22 463.19 28

4-tert-Butyl-N-{3-[8- (4-fluoro-phenylamino)- imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide MF = C₂₉H₂₆FN₅O 479.21 480.10 29

4-tert-Butyl-N-{3-[8- (3-fluoro-phenylamino)- imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide MF = C₂₉H₂₆FN₅O 479.21 480.10 30

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid MF = C₃₀H₂₇N₅O₃ 505.21 506.08 31

4-tert-Butyl-N-{3-[8- (3-methoxy-phenylamino)- imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide MF = C₃₀H₂₉N₅O₂ 491.23 492.08 32

4-tert-Butyl-N-{3-[8- (6-methoxy-pyridin-3- ylamino)-imidazo[1,2-a]pyrazin-6-yl]- phenyl}-benzamide MF = C₂₉H₂₈N₆O₂ 492.22 493.08 33

3-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid MF = C₃₀H₂₇N₅O₃ 505.21 506.25 34

4-{6-[3-(4-Isopropyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid MF = C₂₉H₂₅N₅O₃ 491.19 492.19 35

4-tert-Butyl-N-{3-[8- (4-cyano-phenylamino)- imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide MF = C₃₀H₂₆N₆O 486.22 487.28 36

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzamide MF = C₃₀H₂₈N₆O₂ 504.22 505.21

TABLE II Cmp. MS m/z # STRUCTURE NAME MW (M⁺¹) 37

4-tert-Butyl-N-{3-[8-(4- morpholin-4-yl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C33H34N6O2 546.27 547.11 38

3-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid C30H27N5O3 505.21 506.25 39

4-tert-Butyl-N-{3-[8-(3- fluoro-4-methoxy- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C30H28FN5O2 509.22 510.26 40

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic N-Methyl amide C31H30N6O2 518.24 519.21 41

4-tert-Butyl-N-{3-[8-(4- piperazin-1-yl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C33H35N7O 545.29 546.19 42

4-tert-Butyl-N-[3-(8-m- tolylamino-imidazo[1,2- a]pyrazin-6-yl)-phenyl]-benzamide C30H29N5O 475.23 476.22 43

(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-acetic acid methyl ester C32H31N5O3 533.24 534.22 44

(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-acetic acid C31H29N5O3 519.22 520.22 45

4-tert-Butyl-N-(3-{8-[4- (piperazine-1-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H35N7O2573.28 574.85 46

4-tert-Butyl-N-(3-{8-[4-(2- methoxy-ethoxymethoxy)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C33H35N5O4565.26 566.25 47

4-tert-Butyl-N-{3-[8-(4- hydroxy-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]- phenyl}-benzamide C29H27N5O2 477.22 478.2248

4-tert-Butyl-N-{3-[8-(6- piperazin-1-yl-pyridin-3- ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C32H34N8O 546.28 547.24 49

4-tert-Butyl-N-(3-{8-[4-(4- methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H37N7O559.31 560.26 50

4-tert-Butyl-N-{3-[8-(4- [1,4]diazepan-1-yl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C34H37N7O 559.31 561.17 51

4-tert-Butyl-N-(3-{8-[4-(4- oxo-piperidin-1-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H34N6O2558.27 559.22 52

(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoylamino)- acetic acid methyl ester C33H32N6O4 576.24577.29 53

(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoylamino)- acetic acid C32H30N6O4 562.23 563.26 54

N-(3-{8-[4-(4-Acetyl- piperazin-1-yl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- tert-butyl-benzamide C35H37N7O2 587.3 588.3155

4-tert-Butyl-N-(3-{8-[4-(3- methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H37N7O559.31 560.35 56

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic hydroxyl amide C30H28N6O3 520.22 521.26 57

4-tert-Butyl-N-{3-[8-(4- hydroxymethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C30H29N5O2 491.23 492.28 58

4-tert-Butyl-N-{3-[8-(4- piperazin-1-ylmethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C34H37N7O 559.31 560.37 59

4-{6-[3-(4-Bromo-3-methyl- benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8- ylamino}-benzoic acid C27H20BrN5O3 541.07542.14 60

4-tert-Butyl-N-{3-[8-(3- methyl-4-piperazin-1-yl-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C34H37N7O559.31 560.35 61

4-tert-Butyl-N-(3-{8-[4-(3- methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H37N7O559.31 560.26 62

4-tert-Butyl-N-{3-[8-(3- hydroxymethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C30H29N5O2 491.23 492.28 63

4-tert-Butyl-N-(3-{8-[3-(3- methyl-piperazin-1- ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H39N7O 573.32 574.4 64

4-tert-Butyl-N-(3-{8-[3-(3- methyl-piperazin-1- ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H39N7O 573.32 574.3565

4-tert-Butyl-N-(3-{8-[3-(3,5- dimethyl-piperazin-1-ylmethyl)-phenylamino]- imidazo[1,2-a]pyrazin- 6-yl}-phenyl)-benzamideC36H41N7O 587.33 588.39 66

4-tert-Butyl-N-(3-{8-[4-(3,5- dimethyl-piperazin-1-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}- phenyl)-benzamide C35H39N7O573.32 574.42 67

4-({6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-methyl)-benzoic acid C31H29N5O3 519.22 520.4 68

4-tert-Butyl-N-(3-{8-[4-(3- methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H37N7O559.3 560.47 69

4-(1-Hydroxy-1-methyl- ethyl)-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)- phenyl]-benzamide C28H25N5O2 463.2 464.3670

(3-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-acetic acid C31H29N5O3 519.22 520.4 71

N-[3-(8-Phenylamino- imidazo[1,2-a]pyrazin-6-yl)- phenyl]-terephthalamicacid methyl ester C27H21N5O3 463.16 464.32 72

N-[3-(8-Phenylamino- imidazo[1,2-a]pyrazin-6-yl)- phenyl]-terephthalamicacid C26H19N5O3 449.14 450.36 73

2-(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8- ylamino}-phenyl)-propionic acid ethyl esterC34H35N5O3 561.27 562.45 74

2-(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8- ylamino}-phenyl)-propionic acid C32H31N5O3533.24 534.43 75

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-2-methoxy- benzoic acid methyl ester C32H31N5O4 549.23 550.4276

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-2-methoxy- benzoic acid C31H29N5O4 535.22 536.42 77

4-tert-Butyl-N-{3-[8-(3- methylcarbamoylmethyl-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C32H32N6O2532.26 533.4 78

4-tert-Butyl-N-{3-[8-(4- methylcarbamoylmethyl-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C32H32N6O2532.25 533.41 79

4-tert-Butyl-N-{3-[8-(4- cyclooctylcarbamoylmethyl-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C39H44N6O2628.35 629.51 80

4-tert-Butyl-N-[3-(8-{4- [(diisopropylcarbamoyl)- methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)- phenyl]-benzamide C37H42N6O2 602.34 603.4981

4-tert-Butyl-N-{3-[8-(4- carbamoylmethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C31H30N6O2 518.24 519.48 82

3-(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8- ylamino}-phenyl)-propionic acid C32H31N5O3533.24 534.22 83

4-tert-Butyl-N-(3-{8-[4-(2- hydroxy-ethyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C31H31N5O2 505.25 506.4 84

4-tert-Butyl-N-(3-{8-[4-(2- methylamino-ethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C32H34N6O518.3 519.45 85

4-tert-Butyl-N-{3-[8-(4- methylaminomethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C31H32N6O 504.26 505.43 86

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-2-hydroxy-benzoic acid C30H27N5O4 521.2 522.31

Cmp. MS m/z # STRUCTURE NAME MW (M⁺¹) 87

4-tert-Butyl-N-(3-{8-[4-(1- hydroxy-1-methyl-ethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C32H33N5O2519.26 520.27 88

4-tert-Butyl-N-(3-{8-[4-(2- hydroxy-ethoxy)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C31H31N5O3 521.24 522.25 89

4-tert-Butyl-N-(3-{8-[4-(4- methyl-piperazine-1- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H37N7O2 587.3 588.2890

4-tert-Butyl-N-(3-{8-[4-(2- methylamino-ethoxy)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C32H34N6O2534.27 535.27 91

4-tert-Butyl-N-(3-{8-[4-(2- dimethylamino-ethoxy)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C33H36N6O2548.28 549.28 92

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic methoxy amide C31H30N6O3 534.23 535.25 93

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic hyrdoxyl methyl amide C31H30N6O3 534.23 535.25 94

4-tert-Butyl-N-(3-{8-[4- ([1,4]diazepane-1-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C35H37N7O2587.3 588.27 95

4-tert-Butyl-N-(3-{8-[4- (pyrrolidine-1-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H34N6O2558.27 559.25 96

4-tert-Butyl-N-(3-{8-[4- (morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H34N6O3574.26 575.24 97

4-tert-Butyl-N-(3-{8-[4- (ethoxyamine-4-cabonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C33H34N6O3548.25 549.22 98

4-tert-Butyl-N-(3-{8-[4- (dimethylamine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C32H32N6O2532.25 533.22 99

4-tert-Butyl-N-(3-{8-[4- (methylethylamine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C33H34N6O2 546.27 547.24100

4-tert-Butyl-N-(3-{8-[4-(3- oxo-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H33N7O3587.26 588.28 101

4-tert-Butyl-N-(3-{8- [N,N,N′-Trimethyl-ethane- 1,2-diamine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C35H39N7O2589.31 590.35 102

4-tert-Butyl-N-(3-{8-[4-(4- methyl-[1,4]diazepane-1-carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamideC36H39N7O2 601.31 602.32 103

4-tert-Butyl-N-(3-{8-[4-(N- methyl ethoxyamine-4-carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamideC33H34N6O3 562.26 563.29 104

4-tert-Butyl-N-(3-{8-[4-(4- ethyl-piperazine-1- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C36H39N7O2 601.31 602.38105

4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-ylamino}-benzoic benzyl amide C37H34N6O2 595.26 596.32 106

4-tert-Butyl-N-(3-{8-[4-(4- methyl-piperazin-1- ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H39N7O 573.32 574.39107

4-tert-Butyl-N-(3-{8-[4-(4- ethyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H41N7O587.33 588.42 108

4-tert-Butyl-N-{3-[8-(4- [1,4]diazepan-1-ylmethyl-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C35H39N7O573.32 574.39 109

4-tert-Butyl-N-(3-{8-[4-(3- methyl-piperazin-1- ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H39N7O 573.32 574.38110

4-tert-Butyl-N-{3-[8-(4- dimethylaminomethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C23H34N6O 518.27 519.33 111

4-tert-Butyl-N-[3-(8-{4- [(ethyl-methyl-amino)- methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6- yl)-phenyl]-benzamide C33H36N6O 532.29 533.33112

4-tert-Butyl-N-{3-[8-(4- {[(2-methoxy-ethyl)-methyl- amino]-methyl}-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C34H38N6O2562.31 563.33 113

4-tert-Butyl-N-[3-(8-{4-[(2- methoxy-ethylamino)- methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)- phenyl]-benzamide C33H36N6O2 548.28 549.32114

4-tert-Butyl-N-{3-[8-(4- {[(2-dimethylamino-ethyl)-methyl-amino]-methyl}- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C35H41N7O 575.33 576.39 115

N-(3-{8-[4-(4-Acetyl- piperazine-1-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- tert-butyl-benzamide C36H37N7O3 615.29 616.31116

4-tert-Butyl-N-{3-[8-(4- {[(2-hydroxy-ethyl)-methyl- amino]-methyl}-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C33H36N6O2548.28 549.32 117

4-tert-Butyl-N-[3-(8-{4-[(2- hydroxy-ethylamino)- methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)- phenyl]-benzamide C32H34N6O2 534.27 535.32118

4-tert-Butyl-N-(3-{8-[4-(4- methyl-[1,4]diazepan-1-ylmethyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamideC36H41N7O 587.33 588.37 119

N-[3-(8-{4-[2-(Acetyl- methyl-amino)-ethoxy]- phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-4- tert-butyl-benzamide C34H36N6O3 576.28 577.32120

4-(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8- ylamino}-phenyl)- piperazine-1-carboxylic acidethyl ester C36H39N7O3 617.31 618.31 121

N-(3-{8-[4-(4-Acetyl- piperazin-1-ylmethyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- tert-butyl-benzamide C36H39N7O2 601.31 602.26122

4-tert-Butyl-N-{3-[8-(4- imidazol-1-ylmethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C33H31N7O 541.25 542.27 123

4-tert-Butyl-N-{3-[8-(4- pyrrolidin-1-ylmethyl-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C34H36N6O544.29 545.3 124

N-[3-(8-{4-[(Acetyl-methyl- amino)-methyl]- phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-4- tert-butyl-benzamide C33H34N6O2 546.27 547.33125

4-tert-Butyl-N-[3-(8-{4- [(methanesulfonyl-methyl- amino)-methyl]-phenylamino}-imidazo[1,2- a]pyrazin-6-yl)-phenyl]- benzamide C32H34N6O3S584.24 583.27 126

4-tert-Butyl-N-(3-{8-[4-(3- isopropyl-1-methyl- ureidomethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C35H39N7O2589.31 590.35 127

4-Isopropyl-N-(3-{8-[4- (morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C33H32N6O3560.25 561.28 128

N-{3-[8-(4-{[(2-Hydroxy- ethyl)-methyl-amino]- carbonyl}-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]- phenyl}-4-isopropyl- benzamide C32H32N6O3548.25 549.25 129

N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C30H26N6O3 518.2 519.22130

4-Methyl-N-(3-{8-[4- (morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C31H28N6O3 532.22 533.17 131

4-Ethyl-N-(3-{8-[4- (morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C32H30N6O3 546.23 547.17 132

4-Fluoro-N-(3-{8-[4- (morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C30H25FN6O3 536.19 537.21 133

N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-4-trifluoromethyl- benzamideC31H25F3N6O3 586.19 587.2 134

4-tert-Butyl-N-(3-{8-[4-(5,6- dihydro-8H-imidazo[1,2-a]pyrazine-7-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C36H34N8O2 610.28 611.21 135

4-tert-Butyl-N-(3-{8-[4-(3- oxo-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C34H35N7O2573.28 574.18 136

1-(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8- ylamino}-benzyl)- pyrrolidine-2-carboxylic acidmethyl ester C36H38N6O3 602.3 603.39 137

N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-terephthalamic acid methyl esterC32H28N6O5 576.21 577.36 138

N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-terephthalamic acid C31H26N6O5562.19 563.33

Cmp. MS m/z # STRUCTURE NAME MW (M⁺¹) 139

N-(3-{8-[4-(4-Acetyl- piperazin-1-yl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- ethyl-benzamide C33H33N7O2 559.26 560.25 140

N-(3-{8-[4-(4-Acetyl- piperazin-1-yl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- trifluoromethyl-benzamide C32H28F3N7O2 599.22600.22 141

4-tert-Butyl-N-(3-{8-[4-(3- methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin- 7-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C36H37N9O 611.31 612.41142

4-tert-Butyl-N-(3-{8-[4-(3- methyl-5,6-dihydro-8H- [1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C36H35N9O2 625.29 626.4 143

N-(3-{8-[4-(4-Acetyl- piperazin-1-yl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- isopropyl-benzamide C34H35N7O2 573.28 574.38144

N-(3-{8-[4-(4-Acetyl- piperazine-1-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- isopropyl-benzamide C35H35N7O3 601.28 602.27145

1-(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8- ylamino}-benzyl)- pyrrolidine-2-carboxylic acidC35H36N6O3 588.28 589.25 146

4-Isopropyl-N-(3-{8-[4-(3- methyl-5,6-dihydro-8H- [1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C35H33N9O2 611.27 612.26 147

N-(3-{8-[4-(5,6-Dihydro- 8H-imidazo[1,2-a]pyrazine-7-carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-isopropyl- benzamide C35H32N8O2 596.26 597.26 148

4-Isopropyl-N-(3-{8-[4-(3- oxo-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C33H31N7O3573.24 574.27 149

4-Isopropyl-N-(3-{8-[4-(4- methyl-piperazine-1- carbonyl)-phenylamino]-imidazol[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C34H35N7O2 573.28 574.29150

4-Isopropyl-N-(3-{8-[4-(3- oxo-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C33H33N7O2559.26 560.29 151

N-(3-{8-[4-(4-Acetyl- piperazin-1-ylmethyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- isopropyl-benzamide C35N37N7O2 587.3 588.31152

N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-isonicotinamide C29H25N7O3 519.2520.2 153

N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-nicotinamide C29H25N7O3 519.2520.19 154

4-tert-Butyl-N-(3-{8-[4-(2- morpholin-4-yl-2-oxo- ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H36N6O3 588.28 589.28155

4-tert-Butyl-N-(3-{8-[3-(2- morpholin-4-yl-2-oxo- ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H36N6O3 588.28 589.29156

4-Isopropyl-N-{3-[8-(4- morpholin-4-ylmethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C33H34N6O2 546.27 547.28 157

4-tert-Butyl-N-{3-[8-(4- morpholin-4-ylmethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}- benzamide C34H36N6O2 560.28 561.43 158

N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-2-phenyl-acetamide C31H28N6O3532.22 533.21 159

N-(4-tert-Butyl-phenyl)-3- {8-[4-(morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- benzamide C34H34N6O3 574.27 575.23 160

N-(3-Chloro-benzyl)-3-{8- [4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-benzamide C31H27ClN6O3 566.18567.17 161

4-Cyano-N-(3-{8-[4- (morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C31H25N7O3 543.2 544.32 162

6-Dimethylamino-N-(3-{8- [4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- nicotinamideC31N30N8O3 562.24 563.26 163

N-Methyl-N′-(3-{8-[4- (morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- terephthalamide C32H29N7O4 575.22 576.25 164

N,N-Dimethyl-N′-(3-{8-[4- (morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- terephthalamideC33H31N7O4 589.24 590.26 165

4-Acetyl-N-(3-{8-[4- (morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)- benzamide C32H28N6O4 560.21 561.25 166

4-(1H-Imidazol-2-yl)-N-(3- {8-[4-(morpholine-4- carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C33H28N8O3 584.22 585.31167

2-(3-Isopropyl-phenoxy)-N- (3-{8-[4-(morpholine-4-carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}- phenyl)-acetamideC34H34N6O4 590.26 591.32 168

6-tert-Butyl-N-(3-{8-[4- (morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- nicotinamideC33H33N7O3 575.26 576.24 169

4-(6-{3-[(6-tert-Butyl- pyridine-3-carbonyl)- amino]-phenyl}-imidazo[1,2a]pyrazin-8-ylamino)- benzoic acid C29H26N6O3 506.2 507.21

The compounds disclosed in synthetic Examples 1 to 5 were tested in theBtk biochemical assay described in Example 6 and found to exhibit anIC₅₀ value less than or equal to 1 micromolar certain of these compoundswere found to exhibit an IC₅₀ value less than or equal to 100 nM, andcertain of these compounds exhibited an IC₅₀ value less than or equal to10 nM. Some of the compounds disclosed in synthetic Examples 1 to 5 weretested in the B-cell proliferation assay of Example 8 and determined toexhibit an IC₅₀ value less than or equal to 10 micromolar, certain ofthese compounds exhibited an IC₅₀ value less than or equal to 1micromolar, and certain of these compounds exhibited an IC₅₀ value lessthan or equal to 500 nM in this assay. Certain of these compounds do notinhibit T-cell proliferation and have IC₅₀ values greater than or equalto 5 micromolar when assayed under conditions described in Example 9.The compounds assayed in the Example 8 and Example 9 exhibited IC₅₀values for inhibition of T-cell proliferation that were at least 3-fold,and in some instances 5-fold, or even 10-fold greater than the IC₅₀values of these compounds for inhibition of B-cell proliferation.

Example 6 BIOCHEMICAL BTK ASSAY

A generalized procedure for one standard biochemical Btk Kinase Assayused to test compounds disclosed in this application is as follows.

A master mix minus Btk enzyme is prepared containing 1X Cell Signalingkinase buffer (25 mM Tris-HCl, pH 7.5, 5 mM β-glycerophosphate, 2 mMdithiothreitol, 0.1 mM Na₃VO₄, 10 mM MgCl₂), 0.5 μM Promega PTKBiotinylated peptide substrate 2, and 0.01% BSA. A master mix plus Btkenzyme is prepared containing 1X Cell Signaling kinase buffer, 0.5 μMPTK Biotinylated peptide substrate 2, 0.01% BSA, and 100 ng/well (0.06mU/well) Btk enzyme. Btk enzyme is prepared as follows: full lengthhuman wildtype Btk (accession number NM-000061) with a C₁-terminal V5and 6× His tag was subcloned into pFastBac vector for making baculoviruscarrying this epitope-tagged Btk. Generation of baculovirus was donebased on Invitrogen's instructions detailed in its published protocol“Bac-toBac Baculovirus Expression Systems” (Cat. Nos. 10359-016 and10608-016). Passage 3 virus was used to infect Sf9 cells to overexpressthe recombinant Btk protein. The Btk protein was then purified tohomogeneity using Ni-NTA column. The purity of the final proteinpreparation was greater than 95% based on the sensitive Sypro-Rubystaining. A solution of 200 μM ATP is prepared in water and adjusted topH7.4 with 1N NaOH. A quantity of 1.25 μL of compounds in 5%DMSO istransferred to a 96-well ½ area Costar polystyrene plate. Compounds aretested singly and with an 11-point dose-responsive curve (startingconcentration is 10 μM; 1:2 dilution). A quantity of 18.75 μL of mastermix minus enzyme (as a negative control) and master mix plus enzyme istransferred to appropriate wells in 96-well ½ area costar polystyreneplate. 5 μL of 200 μM ATP is added to that mixture in the 96-well ½ areaCostar polystyrene plate for final ATP concentration of 40 μM. Thereaction is allowed to incubate for 1 hour at room temperature. Thereaction is stopped with Perkin Elmer 1X detection buffer containing 30mM EDTA, 20 nM SA-APC, and 1 nM PT66 Ab. The plate is read usingtime-resolved fluorescence with a Perkin Elmer Envision using excitationfilter 330 nm, emission filter 665 nm, and 2^(nd) emission filter 615nm. IC₅₀ values are subsequently calculated.

Example 7 RAMOS CELL BTK ASSAY

Another generalized procedure for a standard cellular Btk Kinase Assayused to test compounds disclosed in this application is as follows.

Ramos cells are incubated at a density of 0.5×10⁷ cells/ml in thepresence of test compound for 1 hr at 37° C. Cells are then stimulatedby incubating with 10 μg/ml anti-human IgM F(ab)₂ for 5 minutes at 37°C. Cells are pelleted, lysed, and a protein assay is performed on thecleared lysate. Equal protein amounts of each sample are subject toSDS-PAGE and western blotting with either anti-phosphoBtk(Tyr223)antibody (Cell Signaling Technology #3531) to assess Btkautophosphorylation or an anti-Btk antibody (BD Transduction Labs#611116) to control for total amounts of Btk in each lysate.

Example 8 B-CELL PROLIFERATION ASSAY

B-cells are purified from spleens of 8-16 week old Balb/c mice using aB-cell isolation kit (Miltenyi Biotech, Cat # 130-090-862). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic B-cells for 30 min prior to addition of 10 μg/ml of ananti-mouse IgM antibody (Southern Biotechnology Associates Cat #1022-01) in a final volume of 100 μl. Following 24 hr incubation, 1 μCi³h-thymidine is added and plates are incubated an additional 36 hr priorto harvest using the manufacturer's protocol for SPA[³h] thymidineuptake assay system (Amersham Biosciences # RPNQ 0130). SPA-bead basedfluorescence is counted in a microbeta counter (Wallace Triplex 1450,Perkin Elmer).

Example 9 T CELL PROLIFERATION ASSAY

T cells are purified from spleens of 8-16 week old Balb/c mice using aPan T cell isolation kit (Miltenyi Biotech, Cat # 130-090-861). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic T cells in a final volume of 100 μl in flat clear bottomplates precoated for 90 min at 37° C. with 10 μg/ml each of anti-CD3 (BD# 553057) and anti-CD28 (BD # 553294) antibodies. Following 24 hrincubation, 1 μCi ³h-thymidine is added and plates incubated anadditional 36 hr prior to harvest using the manufacturer's protocol forSPA[³h] thymidine uptake assay system (Amersham Biosciences # RPNQ0130). SPA-bead based fluorescence was counted in a microbeta counter(Wallace Triplex 1450, Perkin Elmer).

1. (canceled)
 2. At least one chemical entity of claim 87 wherein A is0.
 3. At least one chemical entity of claim 87 wherein A is
 1. 4. Atleast one chemical entity of claim 87 wherein R₁ is chosen from phenylsubstituted with hydroxy, —CHO, —COOH, —CONH₂, —CONHOH. C₂-C₆ alkenyl,substituted C₂-C₆ alkenyl chosen from mono-, di-, and tri-substitutedC₂-C₆ alkenyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂. C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, and tri-substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di- andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl mono-C C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkylC₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonylmono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C L C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄S C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, andpyridyl substituted with hydroxy, —CHO, —COOH, —CONH₂, —CONHOH,C₂-C₆alkenyl, substituted C₂-C₆ alkenyl chosen from mono-, di-, andtri-substituted C₂-C₆ alkenyl wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkenyl,C₂-C₄alkynyl C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₄alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄ alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₄haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and wherein R₁ is optionallyfurther substituted with 1 or more substituents independently chosenfrom hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 5. Atleast one chemical entity of Claim 4, wherein R₁ is chosen from phenylsubstituted with a group chosen from hydroxy, —CHO, —COOH, —CONH₂ and—CONHOH, and pyridyl substituted with a group chosen from hydroxy, —CHO,—COOH, —CONH₂, and —CONHOH, and wherein R₁ is optionally substitutedwith 1 or more substituents independently chosen from hydroxy, nitro,cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl,(C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆ alkyl, (di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 6. At least onechemical entity of claim 5, wherein R₁ is chosen from phenyl substitutedwith a group chosen from hydroxy, —CHO, —COOH, —CONH₂, and —CONHOH, andpyridyl substituted with a group chosen from hydroxy, —CHO, —COOH,—CONH₂, and —CONHOH, wherein R₁ is optionally further mono- di- ortri-substituted with groups independently chosen from hydroxy, cyano,halogen, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxy, mono-C₁-C₄alkylamino, and C₁-C₄alkylamino.
 7. At least onechemical entity of claim 6, wherein R₁ is chosen from phenyl substitutedwith a group chosen from hydroxy —CHO, —COOH, —CONH₂, and —CONHOH, andpyridyl substituted with a group chosen from hydroxy, —CHO, —COOH,—CONH₂, and —CONHOH, wherein R₁ is optionally further mono-, di- ortri-substituted with groups independently chosen from hydroxy, cyano,halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.
 8. At least one chemical entity ofClaim 4 wherein R₁ is chosen from phenyl substituted with a group chosenfrom C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl,C₁-C₆hydroxyalkoxy, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxyheterocycloalkyl, aryl and heteroaryl each of which groups is optionallymono-, di-, or tri-substituted with substituents independently chosenfrom halogen hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and pyridyl substituted with agroup chosen from, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl chosen frommono-, di-, and tri-substituted C₂-C₆ alkenyl wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆alkynyl, substituted C₂-C₆ alkynyl chosen from mono-, di-, andtri-substituted C₂-C₆ alkynyl wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkyl, C ₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄ alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino; di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylaminomono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄-alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂.C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, of heteroaryl, substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, wherein R₁ is optionally furthersubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 9. Atleast one chemical entity of claim 8 wherein R₁ is chosen from phenylsubstituted with a group chosen from C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl, wherein the substituents are independently chosenfrom halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,C₁-C₆hydroxyalkoxy, substituted C₁-C₆hydroxyalkoxy chosen from mono-,di-, and tri-substituted C₁-C₆hydroxyalkoxy, wherein the substituentsare independently chosen from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (di-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-,di-, and tri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,wherein the substituents are independently chosen from halogen, hydroxy,cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (C₁-C₆alkoxy)(C₁-C₆alkoxy) C₁-C₆alkoxy,substituted (C₁-C₆alkoxyl)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-,di-, and tri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, whereinthe substituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₆alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, pyridyl substituted with a group chosen from,C₁-C₆hydroxyalkyl, substituted C₁-C₆hydroxyalkyl chosen from mono-, di-,and tri-substituted C₁-C₆hydroxyalkyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy, wherein the substituents are independently chosenfrom halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,(mono-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₂alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (di-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-,di-, and tri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,wherein the substituents are independently chosen from halogen, hydroxy,cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy,substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-,di-, and tri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, whereinthe substituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonylmono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, wherein R₁ is optionally further mono-,di- or tri-substituted with substituents independently chosen fromhydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxy, mono-C₁-C₄alkylamino, anddi-C₁-C₄alkylamino.
 10. At least one chemical entity of claim 9 whereinR₁ is chosen from phenyl substituted with a group chosen fromC₁-C₆hydroxyalkyl, C₁-C₆hydroxyalkoxy,(mono-C₁-C₆alkylamino)C₁-C₆alkoxy, (di-C₁-C₆alkylamino)C₁-C₆alkoxy,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, and(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, and pyridyl substituted with agroup chosen from, C₁-C₆hydroxyalkyl, C₁-C₆hydroxyalkoxy,(mono-C₁-C₆alkylamino)C₁-C₆alkoxy, (di-C₁-C₆alkylamino)C₁-C₆alkoxy,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, and(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, wherein R₁ is optionally furthermono-, di- or tri-substituted with substituents independently chosenfrom hydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.
 11. At leastone chemical entity of claim 4 wherein R₁ is chosen from phenylsubstituted with a group chosen from pyrrolidinyl substitutedpyrrolidinyl chosen from mono-, di- and tri-substituted pyrrolidinylwherein the substituents are independently chosen from halogen hydroxy,cyano amino oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinylchosen from mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, piperazinyl,substituted piperazinyl chosen from mono-, di- and tri-substitutedpiperazinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, piperidinyl,substituted piperidinyl chosen from mono-, di- and tri-substitutedpiperidinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,[1,4]diazepanyl, substituted [1,4]diazepanyl chosen from mono-, di- andtri-substituted [1,4]diazepanyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosen frommono-, di- and tri-substituted imidazolyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine,substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen frommono-, di- and tri-substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, wherein the substituentsare independently chosen from halogen, hydroxy, cyano, amino, oxo.—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, and pyridyl substituted with a group chosenfrom pyrrolidinyl, substituted pyrrolidinyl chosen from mono-, di- andtri-substituted pyrrolidinyl, wherein the substituents are independentlychosen from halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, morpholinyl,substituted morpholinyl chosen from mono-, di- and tri-substitutedmorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,thiomorpholinyl, substituted thiomorpholinyl chosen from mono-, di- andtri-substituted thiomorpholinyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1.4]diazepanyl chosen from mono-, di- and tri-substituted[1,4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, phenyl,substituted phenyl chosen from mono-, di- and tri-substituted phenyl,wherein the substituents are independently chosen from halogen, hydroxy,cyano, amino, oxo. —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono- di- and tri-substituted imidazolyl, wherein the substituentsare independently chosen from halogen, hydroxy cyano amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, and5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen, hydroxy, cyanoamino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, R₁ is optionally further mono-, di-, ortri-substituted with substituents independently chosen from hydroxy,cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, mono-C₁-C₄alkylamino, and di-C₁-C₄alkylamino.
 12. Atleast one chemical entity of claim 11, wherein R₁ is chosen from phenylsubstituted with a group chosen from pyrrolidinyl, substitutedpyrrolidinyl chosen from mono- di- and tri-substituted pyrrolidinyl,wherein the substituents are independently chosen from halogen, hydroxy,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, morpholinyl,substituted morpholinyl chosen from mono-, di- and tri-substitutedmorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, thiomorpholinyl, substituted thiomorpholinylchosen from mono-, di- and tri-substituted thiomorpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinylchosen from mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1,4]diazepanyl chosen from mono-, di- and tri-substituted[1.4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono-, di- and tri-substituted imidazolyl, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonylmono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, pyridylsubstituted with a group chosen from, pyrrolidinyl, substitutedpyrrolidinyl chosen from mono-, di- and tri-substituted pyrrolidinyl,wherein the substituents are independently chosen from halogen, hydroxy,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, morpholinyl,substituted morpholinyl chosen from mono-, di- and tri-substitutedmorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH. —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide anddi-C₁-C₄alkylcarboxamide, thiomorpholinyl, substituted thiomorpholinylchosen from mono-, di- and tri-substituted thiomorpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinylchosen from mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1,4]diazepanyl chosen from mono-, di- and tri-substituted[1,4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono-, di- and tri-substituted imidazolyl, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonylmono-C₁-C₄alkylamino, di-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C C₄alkylcarboxamide, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine,and substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosenfrom mono-, di- and tri-substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide. R₁ is optionally further mono-, di-, ortri-substituted with from 0 to 3 substituents independently chosen fromhydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.
 13. At least onechemical entity of claim 4, wherein R₁ is chosen from phenyl substitutedwith a group chosen from —C₁-C₆alkyl(C═O)OR₁₀, substituted—C₁-C₆alkyl(C═O)OR₁₀ chosen from mono-, di-, and tri-substituted—C₁-C₆alkyl(C═O)OR₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkylNR₁₀(SO₂)R₁₁,substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di-, andtri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoylC₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁,substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₁-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, andsubstituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁ R₁₂, wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,pyridyl substituted with a group chosen from, —C₁-C₆alkyl(C═O)OR₁₀,substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen from mono-, di-, andtri-substituted —C C₆alkyl(C═O)OR₁₀ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkylNR₁₀(SO₂)R₁₁,substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di-, andtri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁,substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁ R₁₂substituted —C₀-C₆ alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, R₁ isoptionally further substituted with 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl, andwherein R₁₀, R₁₁, and R₁₂ are independently chosen from hydrogen,hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₇cycloalkyl, and heterocycloalkyl.14. At least one chemical entity claim 13 wherein R₁ is chosen fromphenyl substituted with a group chosen from —C₂-C₄alkyl(C═O)OR₁₀,substituted —C₁-C₄alkyl(C═O)OR₁₀ chosen from mono-, di-, andtri-substituted —C₁-C₄alkyl(C═O)OR₁₀ wherein the substituents areindependently selected from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, —C₀-C₄alkyl(C═O)NR₁₀R₁₁, substituted—C₀-C₄alkyl(C═O)NR₁₀R₁₁ chosen from mono-, di-, and tri-substituted—C₀-C₄alkyl(C═O)NR₁₀R₁₁ wherein the substituents are independentlyselected from halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide. —C₁-C₄alkylNR₁₀(SO₂)R₁₁, substituted—C₁-C₄alkylNR₁₀(SO₂)R₁₁, chosen from mono-, di-, and tri-substituted—C₁-C₄alkylNR₁₀(SO₂)R₁₁ wherein the substituents are independentlyselected from halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —C₀-C₄alkylNR₁₀(C═O)R₁₁, substituted—C₀-C₄alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, and tri-substituted—C₀-C₄alkylNR₁₀(C═O)R₁₁, wherein the substituents are independentlyselected from halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —C₀-C₄alkyl(SO₂)R₁₀, substituted—C₀-C₄alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₄alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂, and substituted—C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, and tri-substituted—C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituents are independentlyselected from halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₂-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, pyridyl substituted with a group chosenfrom —C₁-C₄alkyl(C═O)OR₁₀, substituted —C₁-C₄alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₄alkyl(C═O)R₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,—C₀-C₄alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₄alkyl(C═O)NR₁₀R₁₁ chosen frommono- di- and tri-substituted —C₀-C₄alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,—C₁-C₄alkylNR₁₀(SO₂)R₁, substituted —C₁-C₄alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di- and tri-substituted —C₁-C₄alkylNR₁₁)(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylaminomono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,—C₀-C₄alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₄alkylNR₁₀(C═O)R₁₁ chosen frommono-, di- and tri-substituted —C₀-C₄alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₆alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,—C₀-C₄alkyl(SO₂)R₁₀, substituted —C₀-C₄alkyl(SO₂)R₁₀ chosen from mono-,di- and tri-substituted —C₀-C₄alkyl(SO₂)R₁₀ wherein the substituents areindependently selected from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂ and substituted—C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di- and tri-substituted—C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituents are independentlyselected from halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, wherein R₁ is optionally further mono-, di-,or tri-substituted with from substituents independently chosen fromhydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy, and wherein R₁₀,R₁₁ and R₁₂ are independently chosen from hydrogen, hydroxy, C₁-C₆alkylC₁-C₆alkoxy, C₃-C₁₀cycloalkyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidinyl, and [1.4]diazepanyl.
 15. Atleast one chemical entity of claim 4 wherein R₁ is chosen from phenylsubstituted with -L-G, where L is a group chosen from C₁-C₂alkylene,substituted C₁-C₂alkylene chosen from mono-, di-, and tri-substitutedC₁-C₂alkylene wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonylmono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂ C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthioC₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is a group chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and pyridyl substituted with -L-G,where L is a group chosen from C₁-C₂alkylene, substituted C₁-C₂alkylenechosen from mono-, di-, and tri-substituted C₁-C₂alkylene wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O— chosen from mono-, di-,and tri-substituted C₀-C₂alkylene-O— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted (C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is a group chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₂alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide,and phenyl, wherein R₁ is optionally further substituted with 1 or moresubstituents independently chosen from hydroxy, nitro, cyano, amino,—SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl, C₁-C₂haloalkyl,C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl, (C₁-C₆alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆ alkyl, (di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 16. At least onechemical entity of claim 15, wherein R₁ is chosen from phenylsubstituted with -L-G, where L is a group chosen from C₁-C₂alkylene,substituted C₁-C₂alkylene chosen from mono-, di-, and tri-substitutedC₁-C₂alkylene wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide.C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O— chosen from mono-, di-,and tri-substituted C₀-C₂alkylene-O— wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —(C═O)—, —(C₁-C₂alkylene)(C═O)—, substituted—(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, and tri-substituted—(C₁-C₂alkylene)(C═O)— wherein the substituents are independentlyselected from halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, and G is agroup chosen from pyrrolidinyl, substituted pyrrolidinyl chosen frommono-, di-, and tri-substituted pyrrolidinyl wherein the substituentsare independently selected from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinyl chosenfrom mono-, di-, and tri-substituted morpholinyl wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₄-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di-, and tri-substitutedthiomorpholinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkylC₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, piperazinyl,substituted piperazinyl chosen from mono-, di-, and tri-substitutedpiperazinyl wherein the substituents are, independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, piperidinyl,substituted piperidinyl chosen from mono-, di-, and tri-substitutedpiperidinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,[1,4]diazepanyl, substituted [1.4]diazepanyl chosen from mono-, di-, andtri-substituted [1,4]diazepanyl wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di-, and tri-substituted phenyl wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosen frommono-, di-, and tri-substituted imidazolyl wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide. 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine,substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen frommono-, di- and tri-substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine wherein the substituentsare independently selected from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, and pyridyl substituted with -L-G, where L isa group chosen from C₁-C₂alkylene, substituted C₁-C₂alkylene chosen frommono-, di-, and tri-substituted C₁-C₂alkylene wherein the substituentsare independently selected from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O—chosen from mono-, di-, and tri-substituted C₀-C₂alkylene-O— wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, —(C═O)—, C₁-C₂alkylene)(C═O)—, andsubstituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, and G is a group chosen from pyrrolidinyl,substituted pyrrolidinyl chosen from mono-, di-, and tri-substitutedpyrrolidinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, morpholinyl,substituted morpholinyl chosen from mono-, di-, and tri-substitutedmorpholinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,thiomorpholinyl, substituted thiomorpholinyl chosen from mono-, di-, andtri-substituted thiomorpholinyl wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di-, and tri-substituted piperazinyl wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂-haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di-, and tri-substituted piperidinyl wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1,4]diazepanyl chosen from mono-, di-, and tri-substituted[1,4]diazepanyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁,C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, phenyl,substituted phenyl chosen from mono-, di-, and tri-substituted phenylwherein the substituents are independently selected from halogen,hydroxy, cyano amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono-, di-, and tri-substituted imidazolyl wherein the substituentsare independently selected from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy C₂-C₄ alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine,and substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosenfrom mono-, di- and tri-substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine wherein the substituentsare independently selected from halogen hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, wherein wherein R₁ is optionally furthermono-, di- or tri-substituted with substituents independently chosenfrom hydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxy, mono-C₁-C₄alkylamino, anddi-C₁-C₄alkylamino.
 17. At least one chemical entity of claim 16,wherein R₁ is chosen from phenyl substituted with -L-G, where L is agroup chosen from C₁-C₂alkylene, substituted C₁-C₂alkylene chosen frommono-, di-, and tri-substituted C₁-C₂alkylene wherein the substituentsare independently selected from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —(C═O) —, —(C₁-C₂alkylene)(C═O and substituted—(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, and tri-substituted—(C₁-C₂alkylene)(C═O)— wherein the substituents are independentlyselected from halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, and G is a group chosen from pyrrolidinylsubstituted pyrrolidinyl chosen from mono-, di- and tri-substitutedpyrrolidinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-z C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinyl chosenfrom mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted [1,4]diazepanylchosen from mono-, di- and tri-substituted [1,4]diazepanyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen frommono-, di- and tri-substituted phenyl wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono-, di- and tri-substituted imidazolyl, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄ alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, pyridylsubstituted with -L-G, where L is a group chosen from C₁-C₂alkylene,substituted C₁-C₂alkylene chosen from mono-, di-, and tri-substitutedC₁-C₂alkylene wherein the substituents are independently selected fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O—chosen from mono-, di-, and tri-substituted C₀-C₂alkylene-O— wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, —(C═O)—,—(C₁-C₂alkylene)(C═O)—, substituted —(C₁-C₂alkylene)(C═O)— chosen frommono-, di-, and tri-substituted —(C₁-C₂alkylene)(C═O)— wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, and G is agroup chosen from pyrrolidinyl, substituted pyrrolidinyl chosen frommono-, di- and tri-substituted pyrrolidinyl, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinylchosen from mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₆alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1,4]diazepanyl chosen from mono-, di- and tri-substituted[1,4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen hydroxy oxo, —COOH —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide anddi-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosen frommono-, di- and tri-substituted imidazolyl, wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, R₁ isoptionally further mono-, di-, or tri-substituted with from 0 to 3substituents independently chosen from hydroxy, cyano, halogen,C₁-C₂alkyl, and C₁-C₂alkoxy.
 18. At least one chemical entity of claim17, wherein L is chosen from phenyl substituted with a group chosen from—CH₂—, —(C═O)—, and —(CH₂)(C═O)—, and pyridyl substituted with a groupchosen from —CH₂—, —(C═O)—, and —(CH₂)(C═O)—, G is a group chosen frompyrrolidinyl, substituted pyrrolidinyl chosen from mono-, di- andtri-substituted pyrrolidinyl, wherein the substituents are independentlychosen from halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₂alkyl,C₁-C₂alkoxy, C₂alkanoyl, C₁-C₂alkoxycarbonyl, mono-C₁-C₂alkylamino,di-C₁-C₂alkylamino, mono-C₁-C₂alkylcarboxamide, anddi-C₁-C₂alkylcarboxamide, morpholinyl, substituted morpholinyl chosenfrom mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₂alkyl, C₁-C₂alkoxy, C₂alkanoyl, C₁-C₂alkoxycarbonyl,mono-C₁-C₂alkylamino, di-C₁-C₂alkylamino, mono-C₁-C₂alkylcarboxamide,and di-C₁-C₂alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₂alkyl, C₁-C₂alkoxy,C₂alkanoyl, C₁-C₂alkoxycarbonyl, mono-C₁-C₂alkylamino,di-C₁-C₂alkylamino, mono-C₁-C₂alkylcarboxamide, anddi-C₁-C₂alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₂alkyl, C₁-C₂alkoxy, C₂alkanoyl, C₁-C₂alkoxycarbonyl,mono-C₁-C₂alkylamino, di-C₁-C₆alkylamino, mono-C₁-C₂alkylcarboxamide,and di-C₁-C₂alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen hydroxy, oxo, —COOH,—CONH₂, C₁-C₂alkyl, C₁-C₂alkoxy, C₂alkanoyl, C₁-C₂alkoxycarbonyl,mono-C₁-C₂alkylamino, di-C₁-C₂alkylamino, mono-C₁-C₂alkylcarboxamide,and di-C₁-C₂alkylcarboxamide, [1,4]diazepanyl, and substituted[1,4]diazepanyl chosen from mono-, di- and tri-substituted[1,4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₂alkyl, C₁-C₂alkoxy,C₂alkanoyl, C₁-C₂alkoxycarbonyl, mono-C₁-C₂alkylamino,di-C₁-C₂alkylamino, mono-C₁-C₂alkylcarboxamide, anddi-C₁-C₂alkylcarboxamide, R₁ is optionally further mono-, di-, ortri-substituted with substituents independently chosen from hydroxy,halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.
 19. At least one chemical entityof claim 4, having a structure of Formula 2

wherein R is chosen from hydroxy, —CHO, —COOH, —CONH₂, Of —CONHOH, C₂-C₆alkenyl, substituted C₂-C₆ alkenyl chosen from mono-, di-, andtri-substituted C₂-C₆ alkenyl wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂-haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₄haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₁-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthioC₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₁alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen hydroxyamino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamideand phenyl wherein R₁₀, R₁₁ and R₁₂ are independently chosen fromhydrogen, hydroxy C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₁₀cycloalkyl andheterocycloalkyl and R_(A) is optional and when present each occurrenceis independently chosen from hydroxy, nitro, cyano, amino, —SO₂NH₂,halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy,C₁-C₆ alkylthio, C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆alkylamino)C₀-C₆ alkyl, di-C₁-C₆ alkylamino)C₀-C₆ alkyl, andC₁-C₆alkoxycarbonyl.
 20. At least one chemical entity of claim 19 havinga structure of Formula 3


21. At least one chemical entity of claim 87 wherein R₂ is chosen from(phenyl)C₀-C₂alkyl, substituted (phenyl)C₀-C₂alkyl chosen from mono-,di-, and tri-substituted (phenyl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl, (phenoxy)C₀-C₂alkyl,substituted (phenoxy)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (phenoxy)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl and heteroaryl, (pyridyl)C₀-C₂alkyl, andsubstituted (pyridyl)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (piridyl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl.
 22. At least one chemicalentity of claim 21, wherein R₂ is chosen from (phenyl)C₀-C₂alkyl,substituted (phenyl)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (phenyl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, cyano, amino, halogen, —SO₂NH₂, oxo,—COOH, C₁-C₄alkyl, C₁-C₄ alkoxy, C₂-C₄alkanoyl, C₁-C₄hydroxyalkyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono-C₁-C₆alkylamino,di-C₁-C₆alkylamino, mono-C₁-C₆alkylcarboxamide,di-C₁-C₆alkylcarboxamide, C₁-C₄alkoxycarbonyl, phenyl, and imidazolyl,(phenoxy)C₀-C₂alkyl, substituted (phenoxy)C₀-C₂alkyl chosen from mono-,di-, and tri-substituted (phenoxy)C₀-C₂alkyl wherein the substituentsare independently chosen from hydroxy, cyano, amino, halogen, —SO₂NH₂,oxo, —COOH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄alkanoyl, C₁-C₄hydroxyalkyl,C₁-C₂haloalkyl, C₁-haloalkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₄alkoxycarbonyl, phenyl, and imidazolyl, (pyridyl)C₀-C₂alkyl, andsubstituted (pyridyl)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (pyridyl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, cyano, amino, halogen, —SO₂NH₂, oxo,—COOH. C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄alkanoyl, C₁-C₄hydroxyalkyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono-C₁-C₆alkylamino,di-C₁-C₆alkylamino, mono-C₁-C₆alkylcarboxamide,di-C₁-C₆alkylcarboxamide, C₁-C₄alkoxycarbonyl, phenyl, and imidazolyl.23. At least one chemical entity of claim 87 wherein Z₁ is chosen from

and R₄ is chosen from hydrogen, C₁-C₆alkyl, and C₃-C₇cycloalkyl.
 24. Atleast one chemical entity of claim 23, wherein R₄ is chosen fromhydrogen and of methyl.
 25. At least one chemical entity of claim 4,having a structure of Formula 4


26. At least one chemical entity of claim 25, having a structure ofFormula 5

wherein R is chosen from hydroxy, —CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆alkenyl, substituted C₂-C₆ alkenyl chosen from mono-, di-, andtri-substituted C₂-C₆alkenyl wherein the substituents are independentlyselected from halo en, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino) C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₆alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylaminomono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is C₁-C₂alkylene,substituted C₁-C₂alkylene chosen from mono-, di-, and tri-substitutedC₁-C₂alkylene wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C C₄alkylcarboxamide, and phenyl, and G is heterocycloalkyl,substituted heterocycloalkyl chosen from mono-, di-, and tri-substitutedheterocycloalkyl, wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di- and tri-substituted heteroaryl whereinthe substituents are independently selected from halogen, hydroxy, aminooxo —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylaminomono-C₁-C₄alkylcarboxamide di-C₁-C₄alkylcarboxamide and phenyl, R_(A) isoptional and when present, each occurrence is independently chosen fromhydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₂haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl, andwhere R₁₀, R₁₁, and R₁₂ are independently chosen from hydrogen, hydroxy,C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, and heterocycloalkyl.
 27. Atleast one chemical entity of claim 87 wherein R₃ is chosen from hydrogenand methyl.
 28. At least one chemical entity chosen from compoundshaving a structure of Formula 6

and pharmaceutically acceptable salts, hydrates, solvates, crystalforms, diastereomers, and prodrugs thereof, wherein A is chosen from 0and 1; R₁ is chosen from phenyl, phenyl substituted with a group chosenfrom hydroxy, —CHO. —COOH, —CONH₂, —CONHOH, C₂-C₆ alkenyl, substitutedC₂-C₆ alkenyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkenylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthioC₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₄haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di- andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino) C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy) C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄ alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆alkyl(C═O)NR₁₁R₁₂, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONHC₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtrisubstituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and heteroaryl, heteroarylsubstituted with a group chosen from hydroxy, —CHO, —COOH. —CONH₂,—CONHOH, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl chosen from mono-,di-, and tri-substituted C₂-C₆ alkenyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substitutedC₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthioC₁-C₂haloalkyl, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₀-alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ and substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O NR₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkylC₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄ alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₄haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O), —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenylC₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and wherein R₁₀, R₁₁, and R₁₂ areindependently chosen from hydrogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₁₀cycloalkyl and heterocycloalkyl, and wherein R₁ is furtheroptionally substituted with 1 or more substituents independently chosenfrom hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl; R₃ ischosen from hydrogen, halogen, C₁-C₇ alkyl, heterocycloalkyl,substituted heterocycloalkyl chosen from mono-, di-, and tri-substitutedheterocycloalkyl, wherein the substituents are independently chosen fromhydroxy, nitro, cyano, amino, halogen, —SO₂NH₂, oxo, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆-alkoxy) C₁-C₆ alkoxy,mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl, and—C(O)R₁₄, C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl chosen frommono-, di-, and tri-substituted C₃-C₇cycloalkyl, wherein thesubstituents are independently chosen from hydroxy, nitro, cyano, amino,halogen, —SO₂NH₂, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆-alkoxy)C₁-C₆ alkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,aminoC₁-C₆ alkyl, and —C(O)R₁₄, heteroaryl, and substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl, wherein thesubstituents are independently chosen from hydroxy, nitro, cyano, amino,halogen, —SO₂NH₂, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy C₁-C₂haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆-alkoxy)C₁-C₆ alkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,aminoC₁-C₆ alkyl, and —C(O)R₁₄, Z₁ is chosen from

wherein R₄ is chosen from hydrogen, C₁-C₆alkyl, which is optionallysubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆, alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ here in R₁₄ is chosen fromC₁-C₆ alkyl, C₁-C₃haloalkyl, and phenyl, C₃-C₇cycloalkyl, which isoptionally substituted with 1 or more substituents independently chosenfrom hydroxy, nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ whereinR₁₄ is chosen from C₁-C₆ alkyl, C₁-C₃haloalkyl, and phenyl,heterocycloalkyl, which is optionally substituted with 1 or moresubstituents independently chosen from hydroxy, nitro, cyano, amino,halogen, oxo. C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl, C₁-C₃haloalkyl, andphenyl, phenyl, which is optionally substituted with 1 or moresubstituents independently chosen from hydroxy, nitro, cyano, amino,halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆alkyl, C₁-C₃haloalkyl, andphenyl, and heteroaryl, which is optionally substituted with 1 or moresubstituents independently chosen from hydroxy, nitro, cyano, amino,halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl, C₁-C₃haloalkyl, andphenyl, R₅ is chosen from isopropyl and t-butyl.
 29. At least onechemical entity of claim 28 wherein A is
 0. 30. At least one chemicalentity of claim 28 wherein A is
 1. 31. At least one chemical entity ofclaim 28 wherein R₁ is phenyl phenyl substituted with hydroxy, —CHO,—COOH, —CONH₂. —CONHOH, C₂-C₄alkenyl, substituted C₂-C₆ alkenyl chosenfrom mono-, di-, and tri-substituted C₂-C₆ alkenyl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,C₂-C₆alkynyl, substituted C₂-C₆ alkynyl chosen from mono-, di-, andtri-substituted C₂-C₆ alkynyl wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁C-₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and -L-G, where L is chosen from C₁-C₂alkylene,  substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo. —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  C₀-C₂alkylene-O—,  substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  —(C═O)—,  —(C₁-C₂alkylene)(C═O)—,and  substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen from heterocycloalkyl,  substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonylmono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  C₃-C₇cycloalkyl,  substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  aryl,  substituted aryl chosenfrom mono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  heteroaryl, and  substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, pyridyl, pyridyl substituted withhydroxy, —CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆ alkenyl, substituted C₂-C₆alkenyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkenylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkylC₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄-alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄ alkyl, C₁-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (di-C₁-C₆alkylamino)C₁-C₆alkoxysubstituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₄alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄-alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, and substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and -L-G, where L is chosen from C₁-C₂alkylene,  substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  C₀-C₂alkylene-O—,  substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  —(C═O)—,  —(C₁-C₂alkylene)(C═O)—,and  substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen from heterocycloalkyl,  substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  C₃-C₇cycloalkyl,  substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo. —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl-C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  aryl,  substituted aryl chosenfrom mono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,  heteroaryl, and  substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkylC₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide,and phenyl, wherein R₁ is optionally further substituted with 1 or moresubstituents independently chosen from hydroxy, nitro, cyano, amino,—SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl, C₁-C₄haloalkyl,C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl, (C₁-C₆alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆ alkyl, (di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 32. At least onechemical entity of claim 31, wherein R₁ is chosen from phenylsubstituted with a group chosen from hydroxy, —CHO, —COOH, —CONH₂,—CONHOH, and pyridyl substituted with a group chosen from hydroxy, —CHO,—COOH, —CONH₂, and —CONHOH, and R₁ is optionally further substitutedwith 1 or more substituents independently chosen from hydroxy, nitro,cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl,(C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆ alkyl, (di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 33. At least onechemical entity of claim 32, wherein R₁ is chosen from phenylsubstituted with a group chosen from hydroxy, —CHO —COOH, —CONH ₂, and—CONHOH, and pyridyl substituted with a group chosen from hydroxy, —CHO,—COOH, —CONH₂, and —CONHOH, and R₁ is optionally further mono-, di- ortri-substituted with substituents independently chosen from hydroxy,cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxy, mono-C₁-C₄alkylamino anddi-C₁-C₄alkylamino.
 34. At least one chemical entity of claim 33,wherein R₁ is chosen from phenyl substituted with a group chosen fromhydroxy —CHO —COOH, —CONH₂, and —CONHOH, and pyridyl, substituted with agroup chosen from hydroxy, —CHO, POOH, —CONH₂, and —CONHOH, and R₁ isoptionally further mono-, di-, or tri-substituted with substituentsindependently chosen from hydroxy, cyano, halogen, C₁-C₂alkyl, andC₁-C₂alkoxy.
 35. At least one chemical entity of claim 31 wherein R₁ ischosen from phenyl substituted with a group chosen from C₂-C₆ alkenyl,substituted C₂-C₆ alkenyl chosen from mono-, di-, and tri-substitutedC₂-C₆ alkenyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂. C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄ alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and pyridyl substituted with agroup chosen from, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl chosen frommono-, di-, and tri-substituted C₂-C₆ alkenyl wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆alkynyl, substituted C₂-C₆ alkynyl chosen from mono-, di-, andtri-substituted C₂-C₆alkyl wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkyl C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxyyC₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently, selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heterocycloalkyl substitutedheterocycloalkyl chosen from mono-, di-, and tri-substitutedheterocycloalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, wherein R₁ is optionally furthersubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 36. Atleast one chemical entity of claim 35 wherein R₁ is chosen from phenylsubstituted with a group chosen from C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl, wherein the substituents are independently chosenfrom halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,C₁-C₆hydroxyalkoxy, substituted C₁-C₆hydroxyalkoxy chosen from mono-,di-, and tri-substituted C₁-C₆hydroxyalkoxy, wherein the substituentsare independently chosen from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (di-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,substituted (C₁-C₆alkoxy) (C₁-C₆alkylamino) C₀-C₆alkyl chosen frommono-, di-, and tri-substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy,substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-,di-, and tri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy whereinthe substituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, and pyridyl substituted with a groupchosen from C₁-C₆hydroxyalkyl, substituted C₁-C₆hydroxyalkyl chosen frommono-, di-, and tri-substituted C₁-C₆hydroxyalkyl, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₅-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy, wherein the substituents are independently chosenfrom halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,(mono-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (di-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-,di-, and tri-substituted (C₁-C₆ alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl,wherein the substituents are independently chosen from halogen, hydroxy,cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, (C₁-C₆alkoxy) (C₁-C₆alkoxy)C₁-C₆alkoxy,substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-,di-, and tri-substituted (C₁-C₆ alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, whereinthe substituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, wherein R₁ is optionally further mono-,di-, or tri-substituted with substituents independently chosen fromhydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, mono-C₁-C₄alkoxy, mono-C₁-C₄alkylamino, anddi-C₁-C₄alkylamino.
 37. At least one chemical entity of claim 36 whereinR₁ is chosen from phenyl substituted with C₁-C₆hydroxyalkyl,C₁-C₆hydroxyalkoxy, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,(di-C₁-C₆alkylamino)C₁-C₆alkoxy,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, and(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, and pyridyl, substituted withC₁-C₆hydroxyalkyl, C₁-C₆hydroxyalkoxy,(mono-C₁-C₆alkylamino)C₁-C₆alkoxy, (di-C₁-C₆alkylamino)C₁-C₆alkoxy,(C₁-C₆alkoxy)(C₁-₆alkylamino)C₀-C₆alkyl, and(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, wherein R₁ is optionally furthermono-, di- or tri-substituted with substituents independently chosenfrom hydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.
 38. At leastone chemical entity of claim 31 wherein R₁ is chosen from phenylsubstituted with a group chosen form pyrrolidinyl, substitutedpyrrolidinyl chosen from mono-, di- and tri-substituted pyrrolidinyl,wherein the substituents are independently chosen from halogen, hydroxy,cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinylchosen from mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄ alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, piperazinyl,substituted piperazinyl chosen from mono-, di- and tri-substitutedpiperazinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, piperidinyl,substituted piperidinyl chosen from mono-, di- and tri-substitutedpiperidinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,[1,4]diazepanyl substituted [1,4]diazepanyl chosen from mono-, di- andtri-substituted [1.4]diazepanyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosen frommono-, di- and tri-substituted imidazolyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide. 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine,and substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosenfrom mono-, di- and tri-substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, wherein the substituentsare independently chosen from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, and of pyridyl substituted with a group chosenform pyrrolidinyl, substituted pyrrolidinyl chosen from mono-, di- andtri-substituted pyrrolidinyl, wherein the substituents are independentlychosen from halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, morpholinyl,substituted morpholinyl chosen from mono-, di- and tri-substitutedmorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,thiomorpholinyl, substituted thiomorpholinyl chosen from mono-, di- andtri-substituted thiomorpholinyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1,4]diazepanyl chosen from mono-, di- and tri-substituted[1,4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen frommono-, di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, cyano, amino, oxo. —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, imidazolyl,substituted imidazolyl chosen from mono-, di- and tri-substitutedimidazolyl, wherein the substituents are independently chosen fromhalogen hydroxy, cyano amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen hydroxy, cyano,amino, oxo. —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, wherein R₁ is optionally further mono-,di-, or tri-substituted with from 0 to 3 substituents independentlychosen from hydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono-C₁-C₄alkylamino, anddi-C₁-C₄alkylamino.
 39. At least one chemical entity of claim 38,wherein R₁ is chosen from phenyl substituted with a group chosen frompyrrolidinyl, substituted pyrrolidinyl chosen from mono-, di- andtri-substituted pyrrolidinyl, wherein the substituents are independentlychosen from halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinyl chosenfrom mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide anddi-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted [1,4]diazepanylchosen from mono-, di- and tri-substituted [1,4]diazepanyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, monoC₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosen frommono-, di- and tri-substituted imidazolyl, wherein the substituents areindependently chosen from halogen, hydroxy, oxo. —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, and pyridylsubstituted with a group chosen from pyrrolidinyl substitutedpyrrolidinyl chosen from mono-, di- and tri-substituted pyrrolidinyl,wherein the substituents are independently chosen from halogen, hydroxy,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, morpholinyl,substituted morpholinyl chosen from mono-, di- and tri-substitutedmorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, thiomorpholinyl, substituted thiomorpholinylchosen from mono-, di- and tri-substituted thiomorpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinylchosen from mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1,4]diazepanyl chosen from mono-, di- and tri-substituted[1,4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono-, di- and tri-substituted imidazolyl, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, wherein R₁ is optionally further mono-,di-, or tri-substituted with from substituents independently chosen fromhydroxy, cyano, halogen, C₁-C₂alkyl, and C₁-C₂alkoxy.
 40. At least onechemical entity of claim 31, wherein R₁ is chosen from phenylsubstituted with a group chosen from —C₁-C₆alkyl(C═O)OR₁₀, substituted—C₁-C₆alkyl(C═O)OR₁₀ chosen from mono-, di- and tri-substituted—C₁-C₆alkyl(C═O)OR₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkylNR₁₀(SO₂)R₁₁,substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di-, andtri-substituted —C₁-C₆ alkylNR₁₀(SO₂)R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁,substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ andsubstituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, whereR₁₀, R₁₁, and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,C₁-C₆alkoxy C₃-C₇cycloalkyl, and heterocycloalkyl, and pyridylsubstituted with a group chosen from —C₁-C₆alkyl(C═O)OR₁₀, substituted—C₁-C₆alkyl(C═O)OR₁₀ chosen from mono-, di-, and tri-substituted—C₁-C₆alkyl(C═O)OR₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkylNR₁₀(SO₂)R₁₁,substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di-, andtri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁,substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁R₁₂ andsubstituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, whereR₁₀, R₁₁ and R₁₂ are independently hydrogen, hydroxy, C₁-C₆alkyl,C₁-C₆alkoxy, C₃-C₇cycloalkyl, and heterocycloalkyl, wherein R₁ isoptionally further substituted with 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₂haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-alkylamino)C₀-C₆ alkyl,(di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 41. At leastone chemical entity of claim 40 wherein R₁ is chosen from phenylsubstituted with a group chosen from —C₁-C₄alkyl(C═O)R₁₀, substituted—C₁-C₄alkyl(C═O)OR₁₀ chosen from mono-, di-, and tri-substituted—C₁-C₄alkyl(C═O)OR₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,—C₀-C₄alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₄alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₄alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide. —C₁-C₄alkylNR₁₀(SO₂)R₁₁, substituted—C₁-C₄alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di-, and tri-substituted—C₁-C₄alkylNR₁₀(SO₂)R₁₁ wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide. —C₀-C₄ alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₄alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, and tri-substituted—C₀-C₄alkylNR₁₀(C═O)R₁₁, wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide. —C₀-C₄alkyl(SO₂)R₁₀, substituted—C₁-C₄alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₄alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,—C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂ and substituted —C₀-C₄ alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, where R₁₀, R₁₁, and R₁₂ are independentlychosen from hydrogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, pyrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, and [1.4]diazepanyl, and pyridyl substituted with a groupchosen from —C₁-C₄alkyl(C═O)OR₁₀, substituted —C₁-C₄alkyl(C═O)OR₁₀chosen from mono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ whereinthe substituents are independently selected from halogen, hydroxy,amino, oxo, —COOH, —CONH₂, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide.—C₀-C₄alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₄alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, —C₁-C₄alkylNR₁₀(SO₂)R₁₁, substituted—C₁-C₄alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di-, and tri-substituted—C₁-C₄alkylNR₁₀(SO₂)R₁₁ wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —C₀-C₄alkylNR₁₀(C═O)R₁₁, substituted—C₀-C₄alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, and tri-substituted—C₀-C₄alkylNR₁₀(C═O)R₁₁, wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino; mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —C₀-C₄alkyl(SO₂)R₁₀, substituted—C₀-C₄alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₄alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂ and substituted—C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, and tri-substituted—C₀-C₄alkylNR₁₀(C═O)NR₁₁R₁₂ wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkoxy,C₂-C₄alkanoyl carbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, where R₁₀,R₁₁, and R₁₂ are independently chosen from hydrogen, hydroxy,C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, piperazinyl, piperidinyl, and [1,4]diazepanyl, whereinR₁ is optionally further mono-, di-, or tri-substituted with from 0 to 3substituents independently chosen from hydroxy, cyano, halogen,C₁-C₂alkyl, and C₁-C₂alkoxy.
 42. At least one chemical entity of claim31 wherein R₁ is chosen from phenyl substituted with a group chosen from-L-G, where L is a group chosen from C₁-C₂alkylene, substitutedC₁-C₂alkylene chosen from mono-, di-, and tri-substituted C₁-C₂alkylenewherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl-C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide,and phenyl, C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O— chosen frommono-, di-, and tri-substituted C₀-C₂alkylene-O— wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—(C═O)—, —(C₁-C₂alkylene)(C═O)—, and substituted —(C₁-C₂alkylene)(C═O)—chosen from mono-, di-, and tri-substituted —(C₁-C₂alkylene)(C═O)—wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkylC₁-C₂haloalkoxy carbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, and Gis chosen from heterocycloalkyl substituted heterocycloalkyl chosen frommono-, di-, and tri-substituted heterocycloalkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylaminomono-C₁-C₄alkylcarboxamide di-C₁-C₄alkylcarboxamide, and phenylC₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl chosen from mono-, di-, andtri-substituted C₃-C₇cycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl C₁-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and pyridyl substituted with agroup chosen from -L-G, where L is a group chosen from C₁-C₂alkylene,substituted C₁-C₂alkylene chosen from mono-, di-, and tri-substitutedC₁-C₂alkylene wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, wherein R₁ is optionally furthersubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 43. Atleast one chemical entity of claim 42, wherein R₁ is chosen from phenylsubstituted with -L-G, where L is a group chosen from C₁-C₂alkylene,substituted C₁-C₂alkylene chosen from mono-, di-, and tri-substitutedC₁-C₂alkylene wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄ alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O— chosen from mono-, di-,and tri-substituted C₀-C₂alkylene-O— wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₄ alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, —(C═O)—, —(C₁-C₂alkylene)(C═O)—, substituted—(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, and tri-substituted—(C₁-C₂alkylene)(C═O)— wherein the substituents are independentlyselected from halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, and G is agroup chosen from pyrrolidinyl substituted pyrrolidinyl chosen frommono-, di-, and tri-substituted pyrrolidinyl wherein the substituentsare independently selected from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinyl chosenfrom mono-, di-, and tri-substituted morpholinyl wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di-, and tri-substitutedthiomorpholinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, piperazinylsubstituted piperazinyl chosen from mono-, di-, and tri-substitutedpiperazinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, piperidinyl,substituted piperidinyl chosen from mono-, di-, and tri-substitutedpiperidinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,[1,4]diazepanyl, substituted [1,4]diazepanyl chosen from mono-, di-, andtri-substituted [1,4]diazepanyl wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di-, and tri-substituted phenyl wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosen frommono-, di-, and tri-substituted imidazolyl wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine,substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen frommono-, di- and tri-substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine wherein the substituentsare independently selected from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, and of pyridyl substituted with -L-G, where Lis a group chosen from C₁-C₂alkylene, substituted C₁-C₂alkylene chosenfrom mono-, di-, and tri-substituted C₁-C₂alkylene wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide. —(C═O)—,—(C₁-C₂alkylene)(C═O)—, and substituted —(C₁-C₂alkylene)(C═O)— chosenfrom mono-, di-, and tri-substituted —(C₁-C₂alkylene)(C═O)— wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, and G is a group chosen from pyrrolidinyl,substituted pyrrolidinyl chosen from mono-, di-, and tri-substitutedpyrrolidinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, morpholinyl,substituted morpholinyl chosen from mono-, di-, and tri-substitutedmorpholinyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide,thiomorpholinyl, substituted thiomorpholinyl chosen from mono-, di-, andtri-substituted thiomorpholinyl wherein the substituents areindependently selected from halogen, hydroxy, cyano, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di-, and tri-substituted piperazinyl wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di-, and tri-substituted piperidinyl wherein thesubstituents are independently selected from halogen, hydroxy, cyano,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₂-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1,4]diazepanyl chosen from mono-, di-, and tri-substituted[1,4]diazepanyl wherein the substituents are independently selected fromhalogen, hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, phenyl,substituted phenyl chosen from mono-, di-, and tri-substituted phenylwherein the substituents are independently selected from halogen,hydroxy, cyano, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono-, di-, and tri-substituted imidazolyl wherein the substituentsare independently selected from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine,and substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosenfrom mono-, di- and tri-substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine wherein the substituentsare independently selected from halogen, hydroxy, cyano, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, wherein wherein R₁ is optionally furthermono-, di-, or tri-substituted with substituents independently chosenfrom hydroxy, cyano, halogen, C₁-C₄alkyl, C₂-C₄alkanoyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxy, mono-C₁-C₄alkylamino, anddi-C₁-C₄alkylamino.
 44. At least one chemical entity of claim 43,wherein R₁ is chosen from phenyl substituted with -L-G, where L is agroup chosen from C₁-C₂alkylene, substituted C₁-C₂alkylene chosen frommono-, di-, and tri-substituted C₁-C₂alkylene wherein the substituentsare independently selected from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide. —(C═O)—,—(C₁-C₂alkylene)(C═O)—, and substituted —(C₁-C₂alkylene)(C═O)— chosenfrom mono-, di-, and tri-substituted —(C₁-C₂alkylene)(C═O)— wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, and G is agroup chosen from pyrrolidinyl, substituted pyrrolidinyl chosen frommono-, di- and tri-substituted pyrrolidinyl, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinylchosen from mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl substituted[1,4]diazepanyl chosen from mono-, di- and tri-substituted[1,4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono-, di- and tri-substituted imidazolyl, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, pyridylsubstituted with -L-G, where L is a group chosen from C₁-C₂alkylene,substituted C₁-C₂alkylene chosen from mono-, di-, and tri-substitutedC₁-C₂alkylene wherein the substituents are independently selected fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O—chosen from mono-, di-, and tri-substituted C₀-C₂alkylene-O— wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, —(C═O)—,—(C₁-C₂alkylene)(C═O)—, substituted —(C₁-C₂alkylene)(C═O)— chosen frommono-, di-, and tri-substituted —(C₁-C₂alkylene)(C═O)— wherein thesubstituents are independently selected from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, and G is agroup chosen from pyrrolidinyl substituted pyrrolidinyl chosen frommono-, di- and tri-substituted pyrrolidinyl wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinylchosen from mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halo en, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, [1,4]diazepanyl, substituted[1.4]diazepanyl chosen from mono-, di- and tri-substituted[1,4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, phenyl, substituted phenyl chosen from mono-,di- and tri-substituted phenyl, wherein the substituents areindependently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, imidazolyl, substituted imidazolyl chosenfrom mono-, di- and tri-substituted imidazolyl, wherein the substituentsare independently chosen from halogen, hydroxy, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, and substituted5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine chosen from mono-, di- andtri-substituted 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, whereinthe substituents are independently chosen from halogen, hydroxy, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide, wherein R₁ isoptionally further mono-, di-, or tri-substituted with substituentsindependently chosen from hydroxy, cyano, halogen, C₁-C₂alkyl, andC₁-C₂alkoxy.
 45. At least one chemical entity of claim 44, wherein L ischosen from phenyl substituted with a group chosen from —CH₂—, —(C═O)—,and —(CH₂)(C═O)— and pyridyl substituted with a group chosen from —CH₂—,—(C═O)—, and —(CH₂)(C═O)— and and G is chosen from pyrrolidinyl,substituted pyrrolidinyl chosen from mono-, di- and tri-substitutedpyrrolidinyl, wherein the substituents are independently chosen fromhalogen hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, morpholinyl, substituted morpholinyl chosenfrom mono-, di- and tri-substituted morpholinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, thiomorpholinyl, substitutedthiomorpholinyl chosen from mono-, di- and tri-substitutedthiomorpholinyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C_(l)-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide, anddi-C₁-C₄alkylcarboxamide, piperazinyl, substituted piperazinyl chosenfrom mono-, di- and tri-substituted piperazinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, piperidinyl, substituted piperidinylchosen from mono-, di- and tri-substituted piperidinyl, wherein thesubstituents are independently chosen from halogen, hydroxy, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono —C₁-C₄alkylcarboxamide,and di-C₁-C₄alkylcarboxamide, or [1,4]diazepanyl, and substituted[1,4]diazepanyl chosen from mono-, di- and tri-substituted[1.4]diazepanyl, wherein the substituents are independently chosen fromhalogen, hydroxy, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, and di-C₁-C₄alkylcarboxamide.
 46. At leastone chemical entity of claim 31, having a structure of Formula 7

wherein R is chosen from hydroxy, —CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆alkenyl, substituted C₂-C₆ alkenyl chosen from mono-, di-,tri-substituted C₂-C₆ alkenyl wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynyl,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄-alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁,substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkylcarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁ R₁₂substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆ alkylNR₁₀(C═O)NR₁₁R₁₂ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkyl carboxamide, and phenyl, whereR₁₀, R₁₁, and R₁₂ are independently chosen from hydrogen, hydroxy,C₁-C₆alkyl, C₁-C₆alkoxy, C₃-C₁₀cycloalkyl, and of heterocycloalkyl,-L-G, where L is chosen from C₁-C₂alkylene, substituted C₁-C₂alkylenechosen from mono-, di-, and tri-substituted C₁-C₂alkylene wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O— chosen from mono-, di-,and tri-substituted C₀-C₂alkylene-O— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₂-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl R_(A) is optional and when presenteach occurrence is independently chosen from hydroxy, nitro, cyano,amino, —SO₂NH₂, halogen, C₁-C₆ alkyl, C₂-C₆alkanoyl, C₁-C₂haloalkyl,C₁-C₄haloalkoxy, C₁-C₆ alkylthio, C₃-C₇cycloalkyl, (C₁-C₆alkoxy)C₀-C₆alkyl, (mono-C₁-C₆alkylamino)C₀-C₆ alkyl, (di-C₁-C₆alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl.
 47. At least onechemical entity of claim 46, having a structure of Formula 8


48. At least one chemical entity of claim 47, having a structure ofFormula 9


49. At least one chemical entity of Claim 29, wherein R₃ is chosen fromhydrogen and methyl.
 50. At least one chemical entity of claim 87,wherein the at least one chemical entity exhibits an IC₅₀ of 1micromolar or less in an in vitro biochemical assay of Btk activity. 51.At least one chemical entity of claim 87, wherein the at least onechemical entity exhibits an IC₅₀ of 100 nanomolar or less in an in vitrobiochemical assay of Btk activity.
 52. At least one chemical entity ofclaim 87, wherein the at least one chemical entity exhibits an IC₅₀ of10 nanomolar or less in an in vitro biochemical assay of Btk activity.53. At least one chemical entity of claim 87, wherein the at least onechemical entity exhibits an IC₅₀ of 10 micromolar or less in an assayfor inhibition of B-cell proliferation.
 54. At least one chemical entityof claim 87, wherein the at least one chemical entity exhibits an IC₅₀of 1 micromolar or less in an assay for inhibition of B-cellproliferation.
 55. At least one chemical entity of claim 87, wherein theat least one chemical entity exhibits an IC₅₀ of 500 nanomolar or lessin an assay for inhibition of B-cell proliferation.
 56. At least onechemical entity of claim 87, wherein the at least one chemical entityexhibits an IC₅₀ value in an assay for inhibition of T-cellproliferation that is at least 3-fold greater than an IC₅₀ value the atleast one chemical entity exhibits in an assay for inhibition of B-cellproliferation.
 57. At least one chemical entity of claim 87, wherein theat least one chemical entity exhibits an IC₅₀ value in an assay forinhibition of T-cell proliferation that is at least 5-fold greater thanan IC₅₀ value the at least one chemical entity exhibits in an assay forinhibition of B-cell proliferation.
 58. At least one chemical entity ofclaim 87, wherein the at least one chemical entity exhibits an IC₅₀value in an assay for inhibition of T-cell proliferation that is atleast 10-fold greater than an IC₅₀ value the at least one chemicalentity exhibits in an assay for inhibition of B-cell proliferation. 59.A pharmaceutical composition, comprising at least one chemical entity ofclaim 87, together with at least one pharmaceutically acceptable carrieror excipient.
 60. A pharmaceutical composition of claim 59, wherein thecomposition is formulated as an injectable fluid, an aerosol, a cream, agel, a tablet, a pill, a capsule, a syrup, ophthalmic solution, or atransdermal patch.
 61. A packaged pharmaceutical composition, comprisinga pharmaceutical composition in a container; and instructions for usingthe composition to treat a patient suffering from an disease responsiveto Btk inhibition, wherein the pharmaceutical composition comprises (a)at least one pharmaceutically acceptable carrier or excipient and (b) atleast one chemical entity chosen from compounds of Formula I-a

 and pharmaceutically acceptable salts, hydrates solvates, crystalforms, diastereomers, and prodrugs thereof, wherein A is chosen from 0and 1; R₁ is chosen from phenyl substituted with a group chosen fromhydroxy, —CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆ alkenyl, substituted C₂-C₆alkenyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkenylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,(mono-C₁-C₆_alkylamino)C₁-C₆alkoxy, substituted(mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy) (C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, and,tri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₂-alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkyl(C═O)OR₁₀, substituted—C₁-C₆alkyl(C═O)OR₁₀ chosen from mono-, di-, and tri-substituted—C₁-C₆alkyl(C═O)OR₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkylNR₁₀(SO₂)R₁₁,substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di-, andtri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁,substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, -L-G,where L is chosen from C₁-C₂alkylene, substituted C₁-C₂alkylene chosenfrom mono-, di-, and tri-substituted C₁-C₂alkylene wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylaminomono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O— chosen from mono-, di-,and tri-substituted C₀-C₂alkylene-O— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkenyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₂-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and heteroaryl substituted with agroup chosen from hydroxy, —CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆ alkenyl,substituted C₂-C₆ alkenyl chosen from mono-, di-, and tri-substitutedC₂-C₆ alkenyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₂-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen hydroxy, amino,oxo, —COOH, —CONH₂. C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄-alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₁-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and trisubstituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkenyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide,and phenyl, aryl substituted aryl chosen from mono-, di-, andtri-substituted aryl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and R₁ is optionally furthersubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl; R₂ ischosen from C₁-C₇ alkyl, (C₁-C₆alkoxy)C₀-C₆alkoxy,(heterocycloalkyl)C₀-C₂alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl,(phenyl)C₀-C₂alkyl, substituted (phenyl)C₀-C₂alkyl chosen from mono-,di-, and tri-substituted (phenyl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl and heteroaryl, (phenoxy)C₀-C₂alkyl,substituted (phenoxy)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (phenoxy)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl, (heteroaryl)C₀-C₂alkyl, andsubstituted (heteroaryl)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (heteroaryl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₂haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl Z₁ is chosen from

wherein R₄ is chosen from hydrogen, C₁-C₆alkyl, C₁-C₆alkyl substitutedwith 1 or more substituents independently chosen from hydroxy, nitro,cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl,C₁-C₃haloalkyl and phenyl; C₃-C₇cycloalkyl, C₃-C₇cycloalkyl substitutedwith 1 or more substituents independently chosen from hydroxy, nitro,cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆alkoxy)C₁-C₆alkoxy, aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl,C₁-C₃haloalkyl, and phenyl; heterocycloalkyl, heterocycloalkylsubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, halogen, oxo, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy,C₁-C₆alkylthio, (C₁-C₆alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen fromC₁-C₆ alkyl, C₁-C₃haloalkyl, and phenyl; phenyl, phenyl substituted with1 or more substituents independently chosen from hydroxy, nitro, cyano,amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio,(C₁-C₆alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆alkylamino,di-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆alkyl, C₁-C₃haloalkyl, and phenyl; heteroaryl, heteroaryl substitutedwith 1 or more substituents independently chosen from hydroxy, nitro,cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl,C₁-C₃haloalkyl, and phenyl; Q is chosen from phenyl and pyridyl; and R₃is chosen from hydrogen, halogen, C₁-C₇ alkyl, heterocycloalkyl,substituted heterocycloalkyl chosen from mono-, di-, and tri-substitutedheterocycloalkyl wherein the substituents are independently chosen fromhydroxy, nitro, cyano, amino, halogen, —SO₂NH₂, oxo, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆ alkoxy, mono—C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl, and —C(O)R₁₄,C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl chosen from mono-, di-, andtri-substituted C₃-C₇cycloalkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆alkoxy, mono —C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl and—C(O)R₁₄, heteroaryl, and substituted heteroaryl chosen from mono-, di-,and tri-substituted heteroaryl wherein the substituents areindependently chosen from hydroxy nitro, cyano, amino, halogen, —SO₂NH₂,oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxyC₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆alkoxy mono —C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl, and—C(O)R₁₄.
 62. A packaged pharmaceutical composition, comprising apharmaceutical composition of claim 59 in a container; and instructionsfor using the composition to treat a patient suffering from an diseaseresponsive to Btk inhibition
 63. The packaged pharmaceutical compositionof claim 61 wherein the disease responsive to Btk inhibition is cancer.64. The packaged pharmaceutical composition of claim 61 wherein thedisease responsive to Btk inhibition is an autoimmune disease, aninflammatory disease, or an acute inflammatory reaction.
 65. A methodfor treating a patient having a disease responsive to inhibition of Btkactivity, comprising administering to the patient an effective amount ofat least one chemical entity chosen from compounds of Formula I-a

and pharmaceutically acceptable salts, hydrates, solvates, crystalforms, diastereomers, and prodrugs thereof, wherein A is chosen from 0and 1; R₁ is chosen from phenyl substituted with a group chosen fromhydroxy, —CHO, —COOH, —CONH₂, —CONHOH, —C₂-C₆ alkenyl, substituted C₂-C₆alkenyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkenylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄-alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄-alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₁alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄ alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, and Gis chosen from heterocycloalkyl, substituted heterocycloalkyl chosenfrom mono-, di-, and tri-substituted heterocycloalkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl chosen from mono-, di-, andtri-substituted C₃-C₇cycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂-haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and heteroaryl substituted with agroup chosen from hydroxy, —CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆ alkenyl,substituted C₂-C₆ alkenyl chosen from mono-, di-, and tri-substitutedC₂-C₆ alkenyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₁-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylaminomono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkylC₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄ alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogenshydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and R₁ is optionally furthersubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆, alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl; R₂ ischosen from C₁-C₇ alkyl, (C₁-C₆alkoxy)C₀-C₆alkoxy,(heterocycloalkyl)C₀-C₂alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl,(phenyl)C₀-C₂alkyl, substituted (phenyl)C₀-C₂alkyl chosen from mono-,di-, and tri-substituted (phenyl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl, (phenoxy)C₀-C₂alkyl,substituted (phenoxy)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (phenoxy)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl, (heteroaryl)C₀-C₂alkyl, andsubstituted (heteroaryl)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (heteroaryl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide.C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl Z₁ is chosen from

wherein R₄ is chosen from hydrogen, C₁-C₆alkyl, C₁-C₆alkyl substitutedwith 1 or more substituents independently chosen from hydroxy, nitro,cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆-alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆alkoxy)C₁-C₆alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino,di-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆alkyl, C₁-C₂haloalkyl, and phenyl; C₃-C₇cycloalkyl, C₃-C₇cycloalkylsubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, C₁-C₆ alkoxy)C₁-C₆alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen fromC₁-C₆ alkyl, C₁-C₃haloalkyl, and phenyl; heterocycloalkylheterocycloalkyl substituted with 1 or more substituents independentlychosen from hydroxy, nitro, cyano, amino, halogen, oxo. C₁-C₆ alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ whereinR₁₄ is chosen from C₁-C₆alkyl, C₁-C₃haloalkyl, and phenyl; phenyl,phenyl substituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, halogen, oxo, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen fromC₁-C₆alkyl, C₁-C₃haloalkyl, and phenyl; heteroaryl, heteroarylsubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen fromC₁-C₆alkyl, C₁-C₃haloalkyl, and phenyl; O is chosen from phenyl andpyridyl; and R₃ is chosen from hydrogen, halogen, C₁-C₇ alkyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆alkoxy, mono —C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl, and—C(O)R₁₄, C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl chosen frommono-, di-, and tri-substituted C₃-C₇cycloalkyl wherein the substituentsare independently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃-haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆alkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl, and—C(O)R₁₄, heteroaryl, and substituted heteroaryl chosen from mono-, di-,and tri-substituted heteroaryl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆alkoxy, mono —C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl, and—C(O)R₁₄
 66. A method for treating a patient having a disease responsiveto inhibition of Btk activity, comprising administering an effectiveamount of at least one chemical entity claim 87 to the patient.
 67. Themethod of claim 65 wherein the patient is a human.
 68. The method ofclaim 65 er claim 66 wherein the patient is a cat or dog.
 69. The methodof claim 65 wherein the disease responsive to Btk inhibition is cancer.70. The method of claim 65, wherein the disease responsive to Btkinhibition is an autoimmune disease, an inflammatory disease, or anacute inflammatory reaction.
 71. The method of claim 65 wherein the atleast one chemical entity is administered orally.
 72. The method ofclaim 65 wherein the at least one chemical entity is administeredintravenously, intramuscularly, or parenterally.
 73. A method forincreasing sensitivity of cancer cells to chemotherapy, comprisingadministering to a patient undergoing chemotherapy with achemotherapeutic agent an amount of at least one chemical entity chosenfrom compounds a of Formula I-a, and pharmaceutically acceptable salts,hydrates, solvates, crystal forms, diastereomers, and prodrugs thereof,sufficient to increase the sensitivity of cancer cells to thechemotherapeutic agent wherein Formula I-a is

in which A is chosen from 0 and 1; R₁ is chosen from phenyl substitutedwith a group chosen from hydroxy, —CHO, —COOH, —CONH₂, —CONHOH,C₂-C₆alkenyl, substituted C₂-C₆ alkenyl chosen from mono-, di-, andtri-substituted C₂-C₆alkenyl wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄ alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆, alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy) C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄ alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₄ alkynyl, C₁-C₄alkoxy, C₂-C₄ alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄-alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkyl(C═O)OR₁₀, substituted—C₁-C₆alkyl(C═O)OR₁₀ chosen from mono-, di-, and tri-substituted—C₁-C₆alkyl(C═O)OR₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂-haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(C═O)NR₁₀R₁₁,substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkylNR₁₀(SO₂)R₁₁,substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di-, andtri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁,substituted —C₀-C₆NR₁₀(C═O)R₁₁ chosen from mono-, di-, andtri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-, di-, and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀ wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di-, andtri-substituted —C₀-C₆ alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, -L-G,where L is chosen from C₁-C₂alkylene, substituted C₁-C₂alkylene chosenfrom mono-, di-, and tri-substituted C₁-C₂alkylene wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O— chosen from mono-, di-,and tri-substituted C₀-C₂alkylene-O— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonylmono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and heteroaryl substituted with agroup chosen from hydroxy, —CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆ alkenyl,substituted C₂-C₆ alkenyl chosen from mono-, di-, and tri-substitutedC₂-C₆ alkenyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-6 alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di-, and tri-substituted C₂-C₆ alkynylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkyl wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, monoC₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di-, and tri-substitutedC₁-C₆hydroxyalkoxy wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-,and tri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di-, andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di-, and tri-substituted heteroaryl wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di-, and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di-, and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁(C═O)R₁₁ chosen frommono-, di-, and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently selected from halogen, hydroxy, amino,oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀ chosen from mono-,di-, and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀ wherein the substituentsare independently selected from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, substituted —C₀-C₆alkylNR₀₁(C═O)NR₁₁R₁₂chosen from mono-, di-, and tri-substituted C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonylmono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di-, andtri-substituted C₁-C₂alkylene wherein the substituents are independentlyselected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di-, and tri-substitutedC₀-C₂alkylene-O— wherein the substituents are independently selectedfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,and substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di-, andtri-substituted —(C₁-C₂alkylene)(C═O)— wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-,and tri-substituted heterocycloalkyl, wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di-, and tri-substitutedC₃-C₇cycloalkyl wherein the substituents are independently selected fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di-, and tri-substituted aryl wherein the substituents areindependently selected from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, and substitutedheteroaryl chosen from mono-, di-, and tri-substituted heteroarylwherein the substituents are independently selected from halogen,hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and R₁ is optionally furthersubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆, alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl; R₂ ischosen from C₁-C₇ alkyl, (C₁-C₆alkoxy)C₀-C₆alkoxy,(heterocycloalkyl)C₀-C₂alkyl, (C₃-C₇cycloalkyl)C₀-C₆alkyl,(phenyl)C₀-C₂alkyl, substituted (phenyl)C₀-C₂alkyl chosen from mono-,di-, and tri-substituted (phenyl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆alkyl, C₂-C₄alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₂haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl, (phenoxy)C₀-C₂alkyl,substituted (phenoxy)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (phenoxy)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆ alkoxy)C₁-C₆alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl (heteroaryl)C₀-C₂alkyl andsubstituted (heteroaryl)C₀-C₂alkyl chosen from mono-, di-, andtri-substituted (heteroaryl)C₀-C₂alkyl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen, —SO₂NH₂oxo —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl, C₁-C₃haloalkoxy,C₁-C₆alkylthio, (C₁-C₆alkoxy)C₁-C₆alkoxy aminoC₁-C₆alkyl,mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino, mono-C₁-C₆alkylcarboxamide,di-C₁-C₆alkylcarboxamide, C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and—(C═O)R₁₃ wherein R₁₃ is chosen from C₁-C₆alkyl,(C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl, heterocycloalkyl, phenyl,and heteroaryl Z₁ is chosen from

wherein R₄ is chosen from hydrogen, C₁-C₆alkyl, C₁-C₆alkyl substitutedwith 1 or more substituents independently chosen from hydroxy, nitro,cyano, amino, halogen, oxo. C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃-haloalkoxy, C₁-C₆alkylthio,(C₁-C₆alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl mono-C₁-C₆ alkylamino,di-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆alkyl,C₁-C₃haloalkyl, and phenyl; C₃-C₇cycloalkyl, C₃-C₇cycloalkyl substitutedwith 1 or more substituents independently chosen from hydroxy, nitro,cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₁-C₃-haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl,C₁-C₃-haloalkyl, and phenyl; heterocycloalkyl, heterocycloalkylsubstituted with 1 or more substituents independently chosen fromhydroxy, nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen fromC₁-C₆ alkyl, C₁-C₃haloalkyl, and phenyl; phenyl, phenyl substituted with1 or more substituents independently chosen from hydroxy, nitro, cyano,amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆-alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl,C₁-C₃haloalkyl and phenyl; heteroaryl, heteroaryl substituted with 1 ormore substituents independently chosen from hydroxy, nitro, cyano,amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆alkoxy)C₁-C₆alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆alkyl,C₁-C₃haloalkyl, and phenyl; O is chosen from phenyl and pyridyl; and R₃is chosen from hydrogen, halogen, C₁-C₇ alkyl, heterocycloalkyl,substituted heterocycloalkyl chosen from mono-, di-, and tri-substitutedheterocycloalkyl wherein the substituents are independently chosen fromhydroxy, nitro, cyano, amino, halogen, —SO₂NH₂, oxo, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆ alkoxy,mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆alkyl, and —C(O)R₁₄,C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl chosen from mono-, di-, andtri-substituted C₃-C₇cycloalkyl wherein the substituents areindependently chosen from hydroxy nitro, cyano, amino, halogen, —SO₂NH₂,oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆alkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl, and—C(O)R₁₄, heteroaryl, and substituted heteroaryl chosen from mono-, di-,and tri-substituted heteroaryl wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆-alkoxy)C₁-C₆alkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,aminoC₁-C₆ alkyl, and —C(O)R₁₄
 74. A method of reducing medication errorand enhancing therapeutic compliance of a patient being treated for adisease responsive to Btk inhibition, the method comprising providing apackaged pharmaceutical preparation of claim 61 wherein the instructionsadditionally include contraindication and adverse reaction informationpertaining to the packaged pharmaceutical composition.
 75. A method forincreasing sensitivity of cancer cells to chemotherapy, comprisingadministering to a patient undergoing chemotherapy with achemotherapeutic agent an amount of at least one chemical entity ofclaim 87 sufficient to increase the sensitivity of cancer cells to thechemotherapeutic agent.
 76. A method for inhibiting ATP hydrolysis, themethod comprising contacting cells expressing Btk with at least onechemical entity of claim 87 in an amount sufficient to detectablydecrease the level of ATP hydrolysis in vitro.
 77. The method of claim76 wherein the cells are present in a mammal.
 78. The method of claim 77wherein the mammal is a human.
 79. The method of claim 77 wherein themammal is a cat or dog.
 80. A method for determining the presence of Btkin a sample, comprising contacting the sample with at least one chemicalentity of claim 87 under conditions that permit detection of Btkactivity, detecting a level of Btk activity in the sample, and therefromdetermining the presence or absence of Btk in the sample.
 81. (canceled)82. (canceled)
 83. (canceled)
 84. (canceled)
 85. A method for inhibitingB-cell proliferation comprising contacting cells expressing Btk with atleast one chemical entity of claim 87 in an amount sufficient todetectably decrease Btk activity in vitro.
 86. At least one one chemicalentity chosen from4-tert-Butyl-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide;4-Isopropyl-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide;4-tert-Butyl-N-{3-[8-(pyridin-3-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(4-methoxy-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(pyridin-4-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(4-fluoro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(3-fluoro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid;4-tert-Butyl-N-{3-[8-(3-methoxy-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(6-methoxy-pyridin-3-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;3-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid;4-{6-[3-(4-Isopropyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid;4-tert-Butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzamide;4-tert-Butyl-N-{3-[8-(4-morpholin-4-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;3-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid;4-tert-Butyl-N-{3-[8-(3-fluoro-4-methoxy-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicN-Methyl amide;4-tert-Butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-[3-(8-m-tolylamino-imidazo[2-a]pyrazin-6-yl)-phenyl]-benzamide;(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-aceticacid methyl ester;(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-aceticacid;4-tert-Butyl-N-(3-{8-[4-(piperazine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(2-methoxy-ethoxymethoxy)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[8-(4-hydroxy-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(6-piperazin-1-yl-pyridin-3-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[8-(4-[1,4]diazepan-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{8-[4-(4-oxo-piperidin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoylamino)-aceticacid methyl ester;(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoylamino)-aceticacid;N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-(3-{8-[4-(3-methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoichydroxyl amide;4-tert-Butyl-N-{3-[8-(4-hydroxymethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(4-piperazin-1-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-{6-[3-(4-Bromo-3-methyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid;4-tert-Butyl-N-{3-[8-(3-methyl-4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{8-[4-(3-methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[8-(3-hydroxymethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{8-[3-(3-methyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[3-(3-methyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[3-(3,5-dimethyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(3,5-dimethyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-({6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-methyl)-benzoicacid;4-tert-Butyl-N-(3-{8-[4-(3-methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-(1-Hydroxy-1-methyl-ethyl)-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide;(3-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-aceticacid;N-[3-(8-Phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-terephthalamicacid methyl ester;N-[3-(8-Phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-terephthalamicacid;2-(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-propionicacid ethyl ester;2-(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-propionicacid;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-2-methoxy-benzoicacid methyl ester;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-2-methoxy-benzoicacid;4-tert-Butyl-N-{3-[8-(3-methylcarbamoylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(4-methylcarbamoylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(4-cyclooctylcarbamoylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-[3-(8-{4[(diisopropylcarbamoyl)-methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide;4-tert-Butyl-N-{3-[8-(4-carbamoylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;3-(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-propionicacid;4-tert-Butyl-N-(3-{8-[4-(2-hydroxy-ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(2-methylamino-ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[8-(4-methylaminomethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-2-hydroxy-benzoicacid;4-tert-Butyl-N-(3-{8-[4-(1-hydroxy-1-methyl-ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(2-hydroxy-ethoxy)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(2-methylamino-ethoxy)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(2-dimethylamino-ethoxy)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicmethoxy amide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoichyrdoxyl methyl amide;4-tert-Butyl-N-(3-{8-[4-([1,4]diazepane-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(pyrrolidine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(ethoxyamine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(dimethylamine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(methylethylamine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8[N,N,N′-Trimethyl-ethane-1,2-diamine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(N-methylethoxyamine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicbenzyl amide;4-tert-Butyl-N-(3-{8-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[8-(4-[1,4]diazepan-1-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{8-[4-(3-methyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[8-(4-dimethylaminomethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-[3-(8-{4[(ethyl-methyl-amino)-methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide;4-tert-Butyl-N-{3-[8-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-[3-(8-{4[(2-methoxy-ethylamino)-methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide;4-tert-Butyl-N-{3-[8-(4-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;N-(3-{8-[4-(4-Acetyl-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-{3-[8-(4-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-[3-(8-{4[(2-hydroxy-ethylamino)-methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide;4-tert-Butyl-N-(3-{8-[4-(4-methyl-[1,4]diazepan-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;N-[3-(8-{4-[2-(Acetyl-methyl-amino)-ethoxy]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-4-tert-butyl-benzamide;4-(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-piperazine-1-carboxylicacid ethyl ester;N-(3-{8-[4-(4-Acetyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-{3-[8-(4-imidazol-1-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(4-pyrrolidin-1-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;N-[3-(8-{4[(Acetyl-methyl-amino)-methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-4-tert-butyl-benzamide;4-tert-Butyl-N-[3-(8-{4[(methanesulfonyl-methyl-amino)-methyl]-phenylamino}-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide;4-tert-Butyl-N-(3-{8-[4-(3-isopropyl-1-methyl-ureidomethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-Isopropyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;N-{3-[8-(4-{[(2-Hydroxy-ethyl)-methyl-amino]-carbonyl}-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-4-isopropyl-benzamide;N-(3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-Methyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-Ethyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-Fluoro-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;N-(3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-trifluoromethyl-benzamide;4-tert-Butyl-N-(3-{8-[4-(5,6-dihydro-8H-imidazo[1,2-a]pyrazine-7-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(3-oxo-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;1-(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzyl)-pyrrolidine-2-carboxylicacid methyl ester;N-(3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-terephthalamicacid methyl ester;N-(3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-terephthalamicacid;N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-ethyl-benzamide;N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-trifluoromethyl-benzamide;4-tert-Butyl-N-(3-{8-[4-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[4-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-isopropyl-benzamide;N-(3-{8-[4-(4-Acetyl-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-isopropyl-benzamide;1-(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzyl)-pyrrolidine-2-carboxylicacid; 4-Isopropyl-N-(3-{8-[4-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;N-(3-{8-[4-(5,6-Dihydro-8H-imidazo[1,2-a]pyrazine-7-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-isopropyl-benzamide;4-Isopropyl-N-(3-{8-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-Isopropyl-N-(3-{8-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-Isopropyl-N-(3-{8-[4-(3-oxo-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;N-(3-{8-[4-(4-Acetyl-piperazin-1-ylmethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-isopropyl-benzamide;N-(3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-isonicotinamide;N-(3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-nicotinamide;4-tert-Butyl-N-(3-{8-[4-(2-morpholin-4-yl-2-oxo-ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{8-[3-(2-morpholin-4-yl-2-oxo-ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-Isopropyl-N-{3-[8-(4-morpholin-4-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[8-(4-morpholin-4-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;N-(3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-2-phenyl-acetamide;N-(4-tert-Butyl-phenyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzamide;N-(3-Chloro-benzyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzamide;4-Cyano-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;6-Dimethylamino-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-nicotinamide;N-Methyl-N′-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-terephthalamide;N,N-Dimethyl-N′-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-terephthalamide;4-Acetyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;4-(1H-Imidazol-2-yl)-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide;2-(3-Isopropyl-phenoxy)-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-acetamide;6-tert-Butyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-nicotinamide;and4-(6-{3[(6-tert-Butyl-pyridine-3-carbonyl)-amino]-phenyl}-imidazo[1,2a]pyrazin-8-ylamino)-benzoicacid and pharmaceutically acceptable salts hydrates, solvates, crystalforms, diastereomers, and prodrugs thereof.
 87. At least one chemicalentity chosen from compounds of Formula 1

and pharmaceutically acceptable salts, hydrates, solvates, crystalforms, diastereomers, and prodrugs thereof, wherein A is chosen from 0and 1; R₁ is chosen from substituted phenyl wherein the substituent ischosen from hydroxy, CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆ alkenyl,substituted C₂-C₆ alkenyl chosen from mono-, di- and tri-substitutedC₂-C₆ alkenyl, wherein the substituents are independently chosen fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di- and tri-substituted C₂-C₆ alkynyl,wherein the substituents are independently chosen from halogen, hydroxy,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkyl, substitutedC₁-C₆hydroxyalkyl chosen from mono-, di- and tri-substitutedC₁-C₆hydroxyalkyl, wherein the substituents are independently chosenfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di- and tri-substitutedC₁-C₆hydroxyalkoxy, wherein the substituents are independently chosenfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di- andtri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di- andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di- andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di- andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heterocycloalkyl, substitutedheterocycloalkyl chosen from mono-, di- and tri-substitutedheterocycloalkyl, wherein the substituents are independently chosen fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di- and tri-substituted aryl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di- and tri-substituted heteroaryl, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkyl(C═O)OR₁₀, substituted —C₁-C₆alkyl(C═O)OR₁₀ chosen frommono-, di- and tri-substituted —C₁-C₆alkyl(C═O)OR₁₀, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(C═O)NR₁₀R₁₁, substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen frommono-, di- and tri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₁-C₆alkylNR₁₀(SO₂)R₁₁, substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen frommono-, di- and tri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)R₁₁, substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen frommono-, di- and tri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkyl(SO₂)R₁₀, substituted —C₀-C₆alkyl(SO₂)R₁₀chosen from mono-,di- and tri-substituted —C₀-C₆alkyl(SO₂)R₁₀, wherein the substituentsare independently chosen from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,—C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂chosen from mono-, di- and tri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,wherein the substituents are independently chosen from halogen, hydroxy,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, -L-G, where L is chosen fromC₁-C₂alkylene, substituted C₁-C₂alkylene chosen from mono-, di- andtri-substituted C₁-C₂alkyl, wherein the substituents are independentlychosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₀-C₂alkylene-O—, substitutedC₀-C₂alkylene-O— chosen from mono-, di- and tri-substitutedC₀-C₂alkylene-O—, wherein the substituents are independently chosen fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di- andtri-substituted —(C₁-C₂alkylene)(C═O)—, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-and tri-substituted heterocycloalkyl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di- and tri-substitutedC₃-C₇cycloalkyl, wherein the substituents are independently chosen fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di- and tri-substituted aryl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and heteroaryl, and substitutedheteroaryl chosen from mono-, di- and tri-substituted heteroaryl,wherein the substituents are independently chosen from halogen, hydroxy,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and substituted heteroaryl whereinthe substituent is chosen from oxo, —CHO, —COOH, —CONH₂, —CONHOH, C₂-C₆alkenyl, substituted C₂-C₆ alkenyl chosen from mono-, di- andtri-substituted C₂-C₆ alkenyl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₂-C₆ alkynyl, substituted C₂-C₆alkynyl chosen from mono-, di- and tri-substituted C₂-C₆ alkynyl,wherein the substituents are independently chosen from halogen, hydroxy,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,C₁-C₆hydroxyalkyl, substituted C₁-C₆hydroxyalkyl chosen from mono-, di-and tri-substituted C₁-C₆hydroxyalkyl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₁-C₆hydroxyalkoxy, substitutedC₁-C₆hydroxyalkoxy chosen from mono-, di- and tri-substitutedC₁-C₆hydroxyalkoxy, wherein the substituents are independently chosenfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, (mono-C₁-C₆alkylamino)C₁-C₆alkoxy,substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di- andtri-substituted (mono-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₂-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(di-C₁-C₆alkylamino)C₁-C₆alkoxy, substituted(di-C₁-C₆alkylamino)C₁-C₆alkoxy chosen from mono-, di- andtri-substituted (di-C₁-C₆alkylamino)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, substituted(C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl chosen from mono-, di- andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkylamino)C₀-C₆alkyl, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, substituted(C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy chosen from mono-, di- andtri-substituted (C₁-C₆alkoxy)(C₁-C₆alkoxy)C₁-C₆alkoxy, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,heterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-and tri-substituted heterocycloalkyl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di- and tri-substituted aryl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, heteroaryl, substituted heteroarylchosen from mono-, di- and tri-substituted heteroaryl, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkyl(C═O)OR₁₀, substituted—C₁-C₆alkyl(C═O)OR₁₀ chosen from mono-, di- and tri-substituted—C₁-C₆alkyl(C═O)OR₁₀, wherein the substituents are independently chosenfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(C═O)NR₁₀R₁,substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁ chosen from mono-, di- andtri-substituted —C₀-C₆alkyl(C═O)NR₁₀R₁₁, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₁-C₆alkylNR₁₀(SO₂)R₁,substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁ chosen from mono-, di- andtri-substituted —C₁-C₆alkylNR₁₀(SO₂)R₁₁, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)R₁₁,substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁ chosen from mono-, di- andtri-substituted —C₀-C₆alkylNR₁₀(C═O)R₁₁, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkyl(SO₂)R₁₀, substituted—C₀-C₆alkyl(SO₂)R₁₀chosen from mono-, di- and tri-substituted—C₀-C₆alkyl(SO₂)R₁₀, wherein the substituents are independently chosenfrom halogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂,substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂ chosen from mono-, di- andtri-substituted —C₀-C₆alkylNR₁₀(C═O)NR₁₁R₁₂, wherein the substituentsare independently chosen from halogen, hydroxy, amino, oxo, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl, -L-G,where L is chosen from C₁-C₂alkylene, substituted C₁-C₂alkylene chosenfrom mono-, di- and tri-substituted C₁-C₂alkylene, wherein thesubstituents are independently chosen from halogen, hydroxy, amino, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino,mono-C₁-C₄alkylcarboxamide, di-C₁-C₄alkylcarboxamide, and phenyl,C₀-C₂alkylene-O—, substituted C₀-C₂alkylene-O— chosen from mono-, di-and tri-substituted C₀-C₂alkylene-O—, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, —(C═O)—, —(C₁-C₂alkylene)(C═O)—,substituted —(C₁-C₂alkylene)(C═O)— chosen from mono-, di- andtri-substituted —(C₁-C₂alkylene)(C═O)—, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and G is chosen fromheterocycloalkyl, substituted heterocycloalkyl chosen from mono-, di-and tri-substituted heterocycloalkyl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, C₃-C₇cycloalkyl, substitutedC₃-C₇cycloalkyl chosen from mono-, di- and tri-substitutedC₃-C₇cycloalkyl, wherein the substituents are independently chosen fromhalogen, hydroxy, amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, aryl, substituted aryl chosen frommono-, di- and tri-substituted aryl, wherein the substituents areindependently chosen from halogen, hydroxy, amino, oxo, —COOH, —CONH₂,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, and heteroaryl, and substitutedheteroaryl chosen from mono-, di- and tri-substituted heteroaryl,wherein the substituents are independently chosen from halogen, hydroxy,amino, oxo, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, C₁-C₄alkylthio, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₄alkoxycarbonyl, mono-C₁-C₄alkylamino,di-C₁-C₄alkylamino, mono-C₁-C₄alkylcarboxamide,di-C₁-C₄alkylcarboxamide, and phenyl, wherein R₁₀, R₁₁ , and R₁₂ areindependently chosen from hydrogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy,C₃-C₁₀cycloalkyl, and heterocycloalkyl and wherein R₁ is optionallyfurther substituted with 1 or more substituents independently chosenfrom hydroxy, nitro, cyano, amino, —SO₂NH₂, halogen, C₁-C₆ alkyl,C₂-C₆alkanoyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, C₁-C₆ alkylthio,C₃-C₇cycloalkyl, (C₁-C₆ alkoxy)C₀-C₆alkyl, (mono-C₁-C₆ alkylamino)C₀-C₆alkyl, (di-C₁-C₆ alkylamino)C₀-C₆ alkyl, and C₁-C₆alkoxycarbonyl; R₂ ischosen from C₁-C₇ alkyl, (C₁-C₆alkoxy)C₀-C₆alkoxy, (heterocycloalkyl)C₀-C₂alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, (phenyl)C₀-C₂alkyl, substituted(phenyl)C₀-C₂alkyl selected from mono-, di-, and tri-substituted(phenyl)C₀-C₂alkyl, wherein the substituents are independently chosenfrom hydroxy, nitro, cyano, amino, halogen, —SO₂NH₂, oxo, —COOH, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₂-C₆alkanoyl,C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino,di-C₁-C₆alkylamino, mono-C₁-C₆alkylcarboxamide,di-C₁-C₆alkylcarboxamide, C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and—(C═O)R₁₃ wherein R₁₃ is chosen from C₁-C₆alkyl,(C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl, heterocycloalkyl, phenyl,and heteroaryl; (phenoxy)C₀-C₂alkyl, substituted (phenoxy)C₀-C₂alkylselected from mono-, di-, and tri-substituted (phenoxy)C₀-C₂alkyl,wherein the substituents are independently chosen from hydroxy, nitro,cyano, amino, halogen, —SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆alkoxy, aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl; (heteroaryl)C₀-C₂alkyl,substituted (heteroaryl)C₀-C₂alkyl selected from mono-, di-, andtri-substituted (heteroaryl)C₀-C₂alkyl, wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, —COOH, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆hydroxyalkyl, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy,aminoC₁-C₆alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,mono-C₁-C₆alkylcarboxamide, di-C₁-C₆alkylcarboxamide,C₁-C₆alkoxycarbonyl, phenyl, heteroaryl, and —(C═O)R₁₃ wherein R₁₃ ischosen from C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl, C₁-C₃haloalkyl,heterocycloalkyl, phenyl, and heteroaryl; Z₁ is chosen from

wherein R₄ is chosen from Hydrogen, C₁-C₆alkyl, substituted C₁-C₆alkylwherein the substituent is chosen from hydroxy, nitro, cyano, amino,halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl, C₁-C₃haloalkyl, andphenyl; C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl, wherein thesubstituent is chosen from hydroxy, nitro, cyano, amino, halogen, oxo,C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ whereinR₁₄ is chosen from C₁-C₆ alkyl, C₁-C₃haloalkyl, and phenyl;heterocycloalkyl, substituted heterocycloalkyl, wherein the substituentis chosen from hydroxy, nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C_(l)-C₆ alkoxy, C₁-C₃haloalkyl,C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ whereinR₁₄ is chosen from C₁-C₆ alkyl, C₁-C₃haloalkyl, and phenyl; phenyl,substituted phenyl, wherein the substituent is chosen from hydroxy,nitro, cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆alkylthio, (C₁-C₆ alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆alkylamino, di-C₁-C₆ alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen fromC₁-C₆ alkyl, C₁-C₃haloalkyl, and phenyl; heteroaryl, substitutedheteroaryl, wherein the substituent is chosen from hydroxy, nitro,cyano, amino, halogen, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆alkoxy)C₁-C₆ alkoxy, aminoC₁-C₆ alkyl, mono-C₁-C₆ alkylamino, di-C₁-C₆alkylamino, and —C(O)R₁₄ wherein R₁₄ is chosen from C₁-C₆ alkyl,C₁-C₃haloalkyl, and phenyl; Q is chosen from phenyl and pyridyl; and R₃is chosen from hydrogen, halogen, C₁-C₇ alkyl, heterocycloalkyl,substituted heterocycloalkyl selected from mono-, di-, andtri-substituted heterocycloalkyl, wherein the substituents areindependently chosen from hydroxy, nitro, cyano, amino, halogen,—SO₂NH₂, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio, (C₁-C₆-alkoxy)C₁-C₆alkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino, aminoC₁-C₆ alkyl, and—C(O)R₁₄, C₃-C₇cycloalkyl, substituted C₃-C₇cycloalkyl selected frommono-, di-, and tri-substituted C₃-C₇cycloalkyl, wherein thesubstituents are independently chosen from hydroxy, nitro, cyano, amino,halogen, —SO₂NH₂, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆-alkoxy)C₁-C₆ alkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,aminoC₁-C₆ alkyl, and —C(O)R₁₄, heteroaryl, and substituted heteroarylselected from mono-, di-, and tri-substituted heteroaryl, wherein thesubstituents are independently chosen from hydroxy, nitro, cyano, amino,halogen, —SO₂NH₂, oxo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₆ alkylthio,(C₁-C₆-alkoxy)C₁-C₆ alkoxy, mono-C₁-C₆alkylamino, di-C₁-C₆alkylamino,aminoC₁-C₆ alkyl, and —C(O)R₁₄.